Oxindole Derivatives Carrying An Oxetane Substituent and Use Thereof For Treating Vassopressin-Related Diseases

ABSTRACT

The present invention relates to novel substituted oxindole derivatives, pharmaceutical compositions comprising them, and their use for the treatment of vasopressin-related disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This claims priority to U.S. Patent Application No. 61/781,468, filed on Mar. 14, 2013, and U.S. Patent Application No. 61/862,317, filed on Aug. 5, 2013, the entire contents of all of which are fully incorporated herein by reference.

The present invention relates to novel substituted oxindole derivatives, pharmaceutical compositions comprising them, and their use for the treatment of vasopressin-related disorders.

Vasopressin is an endogenous hormone which exerts various effects on organs and tissues. It is suspected that the vasopressin system is involved in various pathological states such as, for example, heart failure and high blood pressure. At present, three receptors (V1a, V1b or V3 and V2) via which vasopressin mediates its numerous effects are known. Antagonists of these receptors are therefore being investigated as possible new therapeutic approaches for the treatment of diseases (M. Thibonnier, Exp. Opin. Invest. Drugs 1998, 7(5), 729-740; T. Ryckmans, Current Opinion in Drug Discovery & Development 13 (2010), 538-547; G. Decaux et al., Lancet 371 (2008), 1624-1632; R. Lemmens-Gruber, M. Kamyar, Cell. Mol. Life Sci. 63 (2006), 1766-1779).

1-Phenylsulfonyl-1,3-dihydro-2H-indol-2-ones have previously been described as ligands of vasopressin receptors, for example in WO 2005/030755, WO 2006/005609, WO 2006/080574, WO 2008/080970, WO 2008/080971, WO 2008/080972, WO 2008/080973, WO 2009/071687, WO 2009/071689, WO 2009/071690, WO2009/071691, WO 2009/083559, WO 2010/009775 or WO 2010/142739.

Besides the binding affinity for the vasopressin V1b receptor, further properties may be advantageous for the treatment and/or prophylaxis of vasopressin-related disorders, such as, for example:

1.) a selectivity for the vasopressin V1b receptor compared with the vasopressin V1a receptor, i.e. the quotient of the binding affinity for the V1a receptor (Ki(V1a) (determined in the unit “nanomolar (nM)”) and the binding affinity for the V1b receptor (Ki(V1b)) (determined in the unit “nanomolar (nM)”). A larger quotient Ki(V1a)/Ki(V1b) means a greater V1b selectivity; 2.) a selectivity for the vasopressin V1b receptor compared with the vasopressin V2 receptor, i.e. the quotient of the binding affinity for the V2 receptor (Ki(V2) (determined in the unit “nanomolar (nM)”) and the binding affinity for the V1b receptor (Ki(V1b)) (determined in the unit “nanomolar (nM)”). A larger quotient Ki(V2)/Ki(V1b) means a greater V1b selectivity; 3.) a selectivity for the vasopressin V1b receptor compared with the oxytocin OT receptor, i.e. the quotient of the binding affinity for the OT receptor (Ki(OT) (determined in the unit “nanomolar (nM)”) and the binding affinity for the V1b receptor (Ki(V1b)) (determined in the unit “nanomolar (nM)”). A larger quotient Ki(OT)/Ki(V1b) means a greater V1b selectivity. 4.) the metabolic stability, for example determined from the half-lives, measured in vitro, in liver microsomes from various species (e.g. rat or human); 5.) no or only low inhibition of cytochrome P450 (CYP) enzymes: cytochrome P450 (CYP) is the name for a superfamily of heme proteins having enzymatic activity (oxidase). They are also particularly important for the degradation (metabolism) of foreign substances such as drugs or xenobiotics in mammalian organisms. The principal representatives of the types and subtypes of CYP in the human body are: CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4. If CYP 3A4 inhibitors (e.g. grapefruit juice, cimetidine, erythromycin) are used at the same time as medicinal substances which are degraded by this enzyme system and thus compete for the same binding site on the enzyme, the degradation thereof may be slowed down and thus effects and side effects of the administered medicinal substance may be undesirably enhanced; 6.) a suitable solubility in water (in mg/ml); 7.) suitable pharmacokinetics (time course of the concentration of the compound of the invention in plasma or in tissue, for example brain). The pharmacokinetics can be described by the following parameters: half-life (in h), volume of distribution (in l·kg⁻¹), plasma clearance (in l·h⁻¹·kg⁻¹), AUC (area under the curve, area under the concentration-time curve, in ng·h·l⁻¹), oral bioavailability (the dose-normalized ratio of AUC after oral administration and AUC after intravenous administration), the so-called brain-plasma ratio (the ratio of AUC in brain tissue and AUC in plasma); 8.) no or only low blockade of the hERG channel: compounds which block the hERG channel may cause a prolongation of the QT interval and thus lead to serious disturbances of cardiac rhythm (for example so-called “torsade de pointes”). The potential of compounds to block the hERG channel can be determined by means of the displacement assay with radiolabelled dofetilide which is described in the literature (G. J. Diaz et al., Journal of Pharmacological and Toxicological Methods, 50 (2004), 187-199). A smaller IC50 in this dofetilide assay means a greater probability of potent hERG blockade. In addition, the blockade of the hERG channel can be measured by electrophysiological experiments on cells which have been transfected with the hERG channel, by so-called whole-cell patch clamping (G. J. Diaz et al., Journal of Pharmacological and Toxicological Methods, 50 (2004), 187-199).

It was therefore an object of the present invention to provide compounds for the treatment or prophylaxis of various vasopressin-related diseases. The compounds were intended to have a high activity and selectivity, especially a high affinity and selectivity vis-à-vis the vasopressin V1b receptor. In addition, the substance of the invention was intended to have one or more of the aforementioned advantages 1.) to 8.).

The object is achieved by compounds of the formula I

wherein

-   X¹ and X² are N or CH, with the proviso that X¹ and X² are not     simultaneously N; -   X³ is a bond, C₁-C₄-alkylene, C₁-C₄-haloalkylene or CO; -   X⁴ is N or CH; -   X⁵ is C—R¹ or N; -   R¹ and R², independently of each other, are selected from hydrogen,     halogen, cyano, C₁-C₃-alkyl, fluorinated C₁-C₃-alkyl,     C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy and fluorinated C₁-C₃-alkoxy; -   R³ is selected from hydrogen, halogen, cyano, C₁-C₃-alkyl,     fluorinated C₁-C₃-alkyl, C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy,     fluorinated C₁-C₃-alkoxy and hydroxyl; -   R⁴ is selected from C₁-C₃-alkoxy; -   R⁵ is selected from hydrogen and C₁-C₃-alkoxy; -   R⁶ is selected from cyano and halogen; -   R⁷ is selected from hydrogen, halogen and cyano; -   R⁸ and R⁹, independently of each other and independently of each     occurrence, are selected from halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,     C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, with the proviso that R⁸ and R⁹     are not halogen, C₁-C₄-alkoxy or C₁-C₄-haloalkoxy if they are bound     to a carbon atom in α-position to a nitrogen ring atom; or -   two non-geminal radicals R⁸ form together a group —(CH₂)_(n)—, where     n is 1, 2, 3 or 4, where 1 or 2 hydrogen atoms in this group may be     replaced a methyl group; or -   two non-geminal radicals R⁹ form together a group —(CH₂)_(n)—, where     n is 1, 2, 3 or 4, where 1 or 2 hydrogen atoms in this group may be     replaced a methyl group; -   each R¹⁰ is independently selected from halogen, C₁-C₄-alkyl and     C₁-C₄-haloalkyl; -   a is O, 1, 2, 3 or 4; -   b is 0, 1, 2, 3 or 4; and -   c is 0, 1, 2, 3 or 4;     and N-oxides, stereoisomers and the pharmaceutically acceptable     salts thereof, and the compound of the formula I, wherein at least     one of the atoms has been replaced by its stable, non-radioactive     isotope.

In a particular embodiment, the invention relates to compounds I, wherein

-   X¹ and X² are N or CH, with the proviso that X¹ and X² are not     simultaneously N; -   X³ is a bond, C₁-C₄-alkylene, C₁-C₄-haloalkylene or CO; -   X⁴ is N or CH; -   X⁵ is C—R¹ or N; -   R¹, R² and R³, independently of each other, are selected from     hydrogen, halogen, cyano, C₁-C₃-alkyl, fluorinated C₁-C₃-alkyl,     C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy and fluorinated C₁-C₃-alkoxy; -   R⁴ is selected from C₁-C₃-alkoxy; -   R⁵ is selected from hydrogen and C₁-C₃-alkoxy; -   R⁶ is selected from cyano and halogen; -   R⁷ is selected from hydrogen, halogen and cyano; -   R⁸ and R⁹, independently of each other and independently of each     occurrence, are selected from halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,     C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, with the proviso that R⁸ and R⁹     are not halogen, C₁-C₄-alkoxy or C₁-C₄-haloalkoxy if they are bound     to a carbon atom in α-position to a nitrogen ring atom; or -   two non-geminal radicals R⁸ form together a group —(CH₂)_(n)—, where     n is 1, 2, 3 or 4, where 1 or 2 hydrogen atoms in this group may be     replaced a methyl group; or -   two non-geminal radicals R⁹ form together a group —(CH₂)_(n)—, where     n is 1, 2, 3 or 4, where 1 or 2 hydrogen atoms in this group may be     replaced a methyl group; -   each R¹⁰ is independently selected from halogen, C₁-C₄-alkyl and     C₁-C₄-haloalkyl; -   a is 0, 1, 2, 3 or 4; -   b is 0, 1, 2, 3 or 4; and -   c is 0, 1, 2, 3 or 4;     and N-oxides, stereoisomers and the pharmaceutically acceptable     salts thereof, and the compound of the formula I, wherein at least     one of the atoms has been replaced by its stable, non-radioactive     isotope.

Accordingly, the present invention relates to compounds of the formula I (also “compounds I” hereinafter) and the N-oxides, stereoisomers and the pharmaceutically acceptable salts of the compounds I of the compounds I.

In another aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula I or an N-oxide, a stereoisomer or a pharmaceutically acceptable salt thereof, or comprising at least one compound as defined above or below wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope, preferably wherein at least one hydrogen atom has been replaced by a deuterium atom, in combination with at least one pharmaceutically acceptable carrier and/or auxiliary substance.

In yet another aspect, the invention relates to a compound of formula I or an N-oxide, a stereoisomer or a pharmaceutically acceptable salt thereof for use as a medicament.

In yet another aspect, the invention relates to a compound of formula I or an N-oxide, a stereoisomer or a pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of vasopressin-related diseases, especially of disorders which respond to the modulation of the vasopressin receptor, in particular of the V1b receptor.

In yet another aspect, the invention relates to the use of a compound of formula I or of an N-oxide, a stereoisomer or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prophylaxis of vasopressin-related diseases; especially of disorders which respond to the modulation of the vasopressin receptor, in particular of the V1b receptor.

The pharmaceutically acceptable salts of compounds of the formula I, which are also referred to as physiologically tolerated salts, are ordinarily obtainable by reacting the free base of the compounds I of the invention (i.e. of the compounds I according to structural formula I) with suitable acids. Examples of suitable acids are listed in “Fortschritte der Arzneimittelforschung”, 1966, Birkhäuser Verlag, vol. 10, pp. 224-285. These include for example hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, formic acid, maleic acid and fumaric acid.

Halogen in the terms of the present invention is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine and especially fluorine or chlorine.

C₁-C₃-Alkyl is a linear or branched alkyl radical having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl or isopropyl. C₁-C₄-Alkyl is a linear or branched alkyl radical having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

C₁-C₄-Haloalkyl is C₁-C₄-alkyl as defined above wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by a halogen atom. Preferably, C₁-C₄-haloalkyl is fluorinated C₁-C₄-alkyl. This is a straight-chain or branched alkyl group having from 1 to 4, in particular 1 to 3 carbon atoms (=fluorinated C₁-C₃-alkyl), more preferably 1 or 2 carbon atoms (=fluorinated C₁-C₂-alkyl), wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by fluorine atoms, such as in fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, (R)-1-fluoroethyl, (S)-1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoropropyl, (R)-1-fluoropropyl, (S)-1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 1,1-difluoropropyl, 2,2-difluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2-fluoropropyl, 2-fluoro-1-methylethyl, (R)-2-fluoro-1-methylethyl, (S)-2-fluoro-1-methylethyl, 2,2-difluoro-1-methylethyl, (R)-2,2-difluoro-1-methylethyl, (S)-2,2-difluoro-1-methylethyl, 1,2-difluoro-1-methylethyl, (R)-1,2-difluoro-1-methylethyl, (S)-1,2-difluoro-1-methylethyl, 2,2,2-trifluoro-1-methylethyl, (R)-2,2,2-trifluoro-1-methylethyl, (S)-2,2,2-trifluoro-1-methylethyl, 2-fluoro-1-(fluoromethyl)ethyl, 1-(difluoromethyl)-2,2-difluoroethyl, 1-fluorobutyl, (R)-1-fluorobutyl, (S)-1-fluorobutyl, 2-fluorobutyl, 3-fluorobutyl, 4-fluorobutyl, 1,1-difluorobutyl, 2,2-difluorobutyl, 3,3-difluorobutyl, 4,4-difluorobutyl, 4,4,4-trifluorobutyl, etc.

C₁-C₄-Hydroxyalkyl is C₁-C₄-alkyl as defined above wherein one of the hydrogen atoms is replaced by a hydroxyl group. Examples are hydroxymethyl, 1- and 2-hydroxyethyl, 1-, 2- and 3-hydroxy-n-propyl, 1-(hydroxymethyl)-ethyl and the like.

C₁-C₃-Alkoxy is a linear or branched alkyl radical linked via an oxygen atom and having 1 to 3 carbon atoms. Examples are methoxy, ethoxy, n-propoxy and isopropoxy. C₁-C₄-Alkoxy is a linear or branched alkyl radical linked via an oxygen atom and having 1 to 4 carbon atoms. Examples are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert-butoxy.

C₁-C₄-Haloalkoxy is C₁-C₄-alkoxy as defined above wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by a halogen atom. Preferably, C₁-C₄-haloalkoxy is fluorinated C₁-C₄-alkoxy. This is a straight-chain or branched alkoxy group having from 1 to 4, in particular 1 to 3 carbon atoms (=fluorinated C₁-C₃-alkoxy), more preferably 1 or 2 carbon atoms (=fluorinated C₁-C₂-alkoxy), wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by fluorine atoms, such as in fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, (R)-1-fluoroethoxy, (S)-1-fluoroethoxy, 2-fluoroethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1-fluoropropoxy, (R)-1-fluoropropoxy, (S)-1-fluoropropoxy, 2-fluoropropoxy, 3-fluoropropoxy, 1,1-difluoropropoxy, 2,2-difluoropropoxy, 3,3-difluoropropoxy, 3,3,3-trifluoropropoxy, 2-fluoro-1-methylethoxy, (R)-2-fluoro-1-methylethoxy, (S)-2-fluoro-1-methylethoxy, 2,2-difluoro-1-methylethoxy, (R)-2,2-difluoro-1-methylethoxy, (S)-2,2-difluoro-1-methylethoxy, 1,2-difluoro-1-methylethoxy, (R)-1,2-difluoro-1-methylethoxy, (S)-1,2-difluoro-1-methylethoxy, 2,2,2-trifluoro-1-methylethoxy, (R)-2,2,2-trifluoro-1-methylethoxy, (S)-2,2,2-trifluoro-1-methylethoxy, 2-fluoro-1-(fluoromethyl)ethoxy, 1-(difluoromethyl)-2,2-difluoroethoxy, (R)-1-fluorobutoxy, (S)-1-fluorobutoxy, 2-fluorobutoxy, 3-fluorobutoxy, 4-fluorobutoxy, 1,1-difluorobutoxy, 2,2-difluorobutoxy, 3,3-difluorobutoxy, 4,4-difluorobutoxy, 4,4,4-trifluorobutoxy, etc

C₁-C₄-Alkylene is a divalent bridging group, such as CH₂, CH₂CH₂, CH(CH₃), (CH₂)₃, CH(CH₃)CH₂, CH₂CH(CH₃), C(CH₃)₂, (CH₂)₄, CH(CH₃)CH₂CH₂, C(CH₃)₂CH₂, CH₂CH(CH₃)CH₂, CH₂C(CH₃)₂, CH₂CH₂CH(CH₃), CH₂C(CH₃)₂ and the like.

C₁-C₄-Haloalkylene is a divalent C₁-C₄-alkylene bridging group as defined above, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by a halogen atom. Preferably, C₁-C₄-haloalkylene is fluorinated C₁-C₄-alkylene. Examples are CHF, CF₂, CHFCH₂, CF₂CH₂, CH₂CHF, CH₂CF₂CF₂CF₂, CF(CH₃), CH(CF₃), CF(CF₃), CHFCH₂CH₂, CH₂CHFCH₂, CH₂CF₂CH₂, CH₂CH(CF₃)CH₂ and the like.

The compounds of the invention of the formula I and their N-oxides, stereoisomers and pharmacologically acceptable salts may also be present in the form of solvates or hydrates. Solvates mean in the context of the present invention crystalline forms of the compounds I or of their pharmaceutically acceptable salts which comprise solvent molecules incorporated in the crystal lattice. The solvent molecules are preferably incorporated in stoichiometric ratios. Hydrates are a specific form of solvates; the solvent in this case being water.

The statements made hereinafter concerning suitable and preferred features of the invention, especially concerning the radicals R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X¹, X², X³, X⁴, X⁵, a, b, c, and n in the compound I, but also concerning the features of the process of the invention and of the use according to the invention apply both taken on their own as well as preferably in any possible combination with one another.

The compounds I are preferably provided in the form of the free base (i.e. according to structural formula I) or in the form of their acid addition salts.

In a preferred embodiment, R¹, R² and R³, independently of each other, are selected from hydrogen, fluorine, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy and trifluoromethoxy. More preferably, R¹, R² and R³, independently of each other, are selected from hydrogen, fluorine, cyano, methyl and methoxy.

Preferably, R¹ is selected from hydrogen, fluorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy and trifluoromethoxy. More preferably, R¹ is selected from hydrogen, fluorine, methyl and methoxy.

Preferably, R² is selected from hydrogen, fluorine, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy and trifluoromethoxy. More preferably, R² is selected from hydrogen, fluorine, cyano, methyl, methoxy, fluoromethoxy, difluoromethoxy and trifluoromethoxy; especially from hydrogen, fluorine, cyano, methoxy, fluoromethoxy, difluoromethoxy and trifluoromethoxy. In particular, R² is selected from hydrogen, cyano, methyl, methoxy and fluorine; more especially from hydrogen, cyano, methoxy and fluorine.

Preferably, R³ is selected from hydrogen, fluorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl and hydroxyl, and more preferably from hydrogen, fluorine, methyl, fluoromethyl, difluoromethyl and trifluoromethyl. In particular, R³ is selected from hydrogen, fluorine and methyl.

R³ is preferably bound in 3- or 5-position, relative to the 2- and 4-positions of R¹ and R².

Preferably, R⁴ is selected from methoxy and ethoxy, and is in particular methoxy, especially in case that X⁴ is N. In an alternative preferred embodiment, R⁴ is isopropoxy.

Preferably, R⁵ is hydrogen or methoxy, and in particular hydrogen.

Preferably, R⁶ is selected from cyano, fluorine and chlorine.

Preferably, R⁷ is selected from hydrogen and fluorine.

Preferably, each R⁸ is independently selected from halogen and C₁-C₄-alkyl, preferably from F, Cl and CH₃, with the proviso that R⁸ is not halogen if it is bound to a carbon atom in α-position to a nitrogen ring atom, or two non-geminal radicals R⁸ form together a group —CH₂— or —CH₂CH₂—, preferably —CH₂—. More preferably, two non-geminal radicals R⁸ form together a group —CH₂—. The two non-geminal radicals R⁸ forming together a group —CH₂— are preferably bound in 2- and 5-positions, relative to the 4-position of X¹.

Preferably, each R⁹ is independently selected from halogen and C₁-C₄-alkyl, preferably from F, Cl and CH₃, with the proviso that R⁸ is not halogen if it is bound to a carbon atom in α-position to a nitrogen ring atom, or two non-geminal radicals R⁹ form together a group —CH₂— or —CH₂CH₂—, preferably —CH₂—. More preferably, two non-geminal radicals R⁹ form together a group —CH₂—. The two non-geminal radicals R⁹ forming together a group —CH₂— are preferably bound in 2- and 5-positions, relative to the 1-position of X².

Preferably, each R¹⁰ is independently selected from halogen and C₁-C₄-alkyl, preferably from F, Cl and CH₃, and is in particular CH₃.

In one embodiment, X¹ is N and X² is CH.

In another embodiment, X¹ is CH and X² is N.

In another embodiment, X¹ is CH and X² is CH.

Preferably, X³ is a bond or CH₂. Specifically, X³ is a bond.

X⁴ is N or CH. Specifically, X⁴ is N.

X⁵ is C—R¹ or N. Specifically, X⁵ is C—R¹.

Preferably, a is 0, 1 or 2, in particular 0 or 2.

Preferably, b is 0, 1 or 2, in particular 0 or 2.

Preferably, c is 0, 1 or 2, more preferably 0 or 1, in particular 0.

The invention preferably relates to compounds of the formula I in which

-   R¹, R² and R³, independently of each other, are selected from     hydrogen, fluorine, cyano, methyl and methoxy; -   R⁴ is selected from methoxy, ethoxy and isopropoxy; in particular     methoxy and ethoxy; -   R⁵ is hydrogen or methoxy; -   R⁶ is selected from cyano, fluorine and chlorine; -   R⁷ is hydrogen or fluorine; -   each R⁸ is independently selected from halogen and C₁-C₄-alkyl or     two non-geminal radicals R⁸ form together a group —CH₂— or —CH₂CH₂—; -   each R⁹ is independently selected from halogen and C₁-C₄-alkyl or     two non-geminal radicals R⁹ form together a group —CH₂— or —CH₂CH₂—; -   each R¹⁰ is independently selected from halogen and C₁-C₄-alkyl; -   X¹ is N or CH; -   X² is N or CH; -   where X¹ and X² are not simultaneously N; -   X³ is a bond or CH₂; -   X⁴ is N or CH; -   X⁵ is C—R¹ or N; -   a is 0, 1 or 2; -   b is 0, 1 or 2; -   c is 0, 1 or 2;     and the pharmaceutically acceptable salts thereof.

The invention more preferably relates to compounds of the formula I in which

-   R¹ is selected from hydrogen, fluorine, methyl and methoxy; -   R² is selected from hydrogen, cyano, methyl, methoxy and fluorine; -   R³ is selected from hydrogen, fluorine and methyl; -   R⁴ is selected from methoxy, ethoxy and isopropoxy; -   R⁵ is hydrogen or methoxy; -   R⁶ is selected from cyano, fluorine and chlorine; -   R⁷ is hydrogen or fluorine; -   each R⁸ is independently selected from F, Cl and methyl, or two     non-geminal radicals R⁸ form together a group —CH₂—; -   each R⁹ is independently selected from F, Cl and methyl, or two     non-geminal radicals R⁹ form together a group —CH₂—; -   each R¹⁰ is independently selected from F, Cl and methyl; -   X¹ is N or CH; -   X² is N or CH; -   where X¹ and X² are not simultaneously N; -   X³ is a bond or CH₂; -   X⁴ is N or CH; -   X⁵ is C—R¹ or N; -   a is 0, 1 or 2, preferably 0 or 2; -   b is 0, 1 or 2, preferably 0 or 2; -   c is 0, 1 or 2, preferably 0 or 1;     and the pharmaceutically acceptable salts thereof. -   The invention more preferably relates to compounds of the formula I     in which -   R¹ is selected from hydrogen, fluorine, methyl and methoxy; -   R² is selected from hydrogen, cyano, methoxy and fluorine; -   R³ is selected from hydrogen, fluorine and methyl; -   R⁴ is selected from methoxy and ethoxy; -   R⁵ is hydrogen or methoxy; -   R⁶ is selected from cyano, fluorine and chlorine; -   R⁷ is hydrogen or fluorine; -   each R⁸ is independently selected from F, Cl and methyl or two     non-geminal radicals R⁸ form together a group —CH₂—; -   each R⁹ is independently selected from F, Cl and methyl or two     non-geminal radicals R⁹ form together a group —CH₂—; -   each R¹⁰ is independently selected from F, Cl and methyl; -   X¹ is N or CH; -   X² is N or CH; -   where X¹ and X² are not simultaneously N; -   X³ is a bond or CH₂; -   X⁴ is N or CH; -   X⁵ is C—R¹ or N; -   a is 0, 1 or 2, preferably 0 or 2; -   b is 0, 1 or 2, preferably 0 or 2; -   c is 0, 1 or 2, preferably 0;     and the pharmaceutically acceptable salts thereof.

The invention more preferably relates to compounds of the formula I in which

-   R¹ is selected from hydrogen, fluorine, methyl and methoxy; -   R² is selected from hydrogen, cyano and methoxy; -   R³ is selected from hydrogen, fluorine and methyl; -   R⁴ is selected from methoxy and ethoxy; -   R⁵ is hydrogen; -   R⁶ is selected from cyano, fluorine and chlorine; -   R⁷ is hydrogen or fluorine; -   each R⁸ is independently selected from F, Cl and methyl or two     non-geminal radicals R⁸ form together a group —CH₂—; -   each R⁹ is independently selected from F, Cl and methyl or two     non-geminal radicals R⁹ form together a group —CH₂—; -   each R¹⁰ is independently selected from F, Cl and methyl; -   X¹ is N or CH; -   X² is N or CH; -   where X¹ and X² are not simultaneously N; -   X³ is a bond or CH₂; -   X⁴ is N or CH; -   X⁵ is C—R¹ or N; -   a is 0, 1 or 2, preferably 0; -   b is 0, 1 or 2, preferably 0 or 2; -   c is 0, 1 or 2, preferably 0;     and the pharmaceutically acceptable salts thereof.

The invention particularly relates to compounds of the formula I in which

-   R¹ is selected from hydrogen, fluorine, methyl and methoxy; -   R² is selected from hydrogen, cyano, methyl, methoxy and fluorine; -   R³ is selected from hydrogen, fluorine and methyl; -   R⁴ is selected from methoxy, ethoxy and isopropoxy, in particular     from methoxy and ethoxy, and is specifically methoxy; -   R⁵ is hydrogen or methoxy, in particular hydrogen; -   R⁶ is selected from cyano, fluorine and chlorine; -   R⁷ is hydrogen or fluorine; -   two non-geminal radicals R⁸ form together a group —CH₂—; -   two non-geminal radicals R⁹ form together a group —CH₂—; -   R¹⁰ is methyl; -   X¹ is N or CH; -   X² is N or CH; -   where X¹ and X² are not simultaneously N; -   X³ is a bond or CH₂; -   X⁴ is N or CH; -   X⁵ is C—R¹ or N; -   a is 0 or 2; -   b is 0 or 2; -   c is 0 or 1;     and the pharmaceutically acceptable salts thereof.

The invention particularly relates to compounds of the formula I in which

-   R is selected from hydrogen, fluorine, methyl and methoxy; -   R² is selected from hydrogen, cyano and methoxy; -   R³ is selected from hydrogen, fluorine and methyl; -   R⁴ is selected from methoxy and ethoxy, in particular from methoxy; -   R⁵ is hydrogen; -   R⁶ is selected from cyano, fluorine and chlorine; -   R⁷ is hydrogen or fluorine; -   two non-geminal radicals R⁸ form together a group —CH₂—; -   two non-geminal radicals R⁹ form together a group —CH₂—; -   X¹ is N or CH; -   X² is N or CH; -   where X¹ and X² are not simultaneously N; -   X³ is a bond or CH₂; -   X⁴ is N; -   X⁵ is C—R¹; -   a is 0 or 2; -   b is 0 or 2; -   c is 0;     and the pharmaceutically acceptable salts thereof.

The invention particularly relates to compounds of the formula I in which

-   R¹ is selected from hydrogen, fluorine, methyl and methoxy; -   R² is selected from hydrogen, cyano and methoxy; -   R³ is selected from hydrogen, fluorine and methyl; -   R⁴ is selected from methoxy and ethoxy; -   R⁵ is hydrogen; -   R⁶ is selected from cyano, fluorine and chlorine; -   R⁷ is hydrogen or fluorine; -   two non-geminal radicals R⁸ form together a group —CH₂—; -   two non-geminal radicals R⁹ form together a group —CH₂—; -   X¹ is N or CH; -   X² is N or CH; -   where X¹ and X² are not simultaneously N; -   X³ is a bond or CH₂; -   X⁴ is CH; -   X⁵ is C—R¹; -   a is 0 or 2; -   b is 0 or 2; -   c is 0;     and the pharmaceutically acceptable salts thereof.

The invention particularly relates to compounds of the formula I in which

-   R¹ is selected from hydrogen, fluorine, methyl and methoxy; -   R² is selected from hydrogen, cyano and methoxy; -   R³ is selected from hydrogen, fluorine and methyl; -   R⁴ is selected from methoxy and ethoxy, in particular from methoxy; -   R⁵ is hydrogen; -   R⁶ is selected from cyano, fluorine and chlorine; -   R⁷ is hydrogen or fluorine; -   two non-geminal radicals R⁸ form together a group —CH₂—; -   two non-geminal radicals R⁹ form together a group —CH₂—; -   X¹ is N or CH; -   X² is N or CH; -   where X¹ and X² are not simultaneously N; -   X³ is a bond or CH₂; -   X⁴ is N; -   X⁵ is N; -   a is 0 or 2; -   b is 0 or 2; -   c is 0;     and the pharmaceutically acceptable salts thereof.

The invention particularly relates to compounds of the formula I in which

-   R¹ is selected from hydrogen, fluorine, methyl and methoxy; -   R² is selected from hydrogen, cyano and methoxy; -   R³ is selected from hydrogen, fluorine and methyl; -   R⁴ is selected from methoxy and ethoxy; -   R⁵ is hydrogen; -   R⁶ is selected from cyano, fluorine and chlorine; -   R⁷ is hydrogen or fluorine; -   two non-geminal radicals R⁸ form together a group —CH₂—; -   two non-geminal radicals R⁹ form together a group —CH₂—; -   X¹ is N or CH; -   X² is N or CH; -   where X¹ and X² are not simultaneously N; -   X³ is a bond or CH₂; -   X⁴ is CH; -   X⁵ is N; -   a is 0 or 2; -   b is 0 or 2; -   c is 0;     and the pharmaceutically acceptable salts thereof.

Examples of preferred embodiment of the present invention are compounds of the formulae I.1 to I.84 and the N-oxides, stereoisomers and the pharmaceutically acceptable salts thereof, in which the radicals R¹, R², R³, R⁶ and R⁷ have one of the above general or preferred meanings, R^(8a), R^(8b), R^(8c) and R^(8d) are hydrogen or have one of the general or preferred meanings given above for R⁸, R^(9a), R^(9b), R^(9c) and R^(9d) are hydrogen or have one of the general or preferred meanings given above for R⁹, and R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen or have one of the general or preferred meanings given above for R¹⁰. In particular, preferred compounds are the individual compounds compiled in the tables 1 to 2520 below. Moreover, the meanings mentioned below for the individual variables in the tables are per se, independently of the combination in which they are mentioned, a particularly preferred embodiment of the substituents in question.

Table 1

Compounds of the formula I.1 in which R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 2

Compounds of the formula I.1 in which R^(8a) is methyl R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 3

Compounds of the formula I.1 in which R^(8b) is methyl, R^(8a), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 4

Compounds of the formula I.1 in which R^(8a) and R^(8b) are methyl, R^(8e), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 5

Compounds of the formula I.1 in which R^(8a) and R^(8c) are methyl, R^(8b), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 6

Compounds of the formula I.1 in which R^(8a) and R^(8d) are methyl, R^(8b), R^(8c), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 7

Compounds of the formula I.1 in which R^(8a) and R^(8c) form together a group —CH₂—, R^(8b), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 8

Compounds of the formula I.1 in which R^(9a) is methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 9

Compounds of the formula I.1 in which R^(9b) is methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 10

Compounds of the formula I.1 in which R^(9a) and R^(9b) are methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 11

Compounds of the formula I.1 in which R^(9a) and R^(9c) are methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 12

Compounds of the formula I.1 in which R^(9a) and R^(9d) are methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 13

Compounds of the formula I.1 in which R^(9a) is fluorine, R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 14

Compounds of the formula I.1 in which R^(9a) and R^(9d) are fluorine, R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 15

Compounds of the formula I.1 in which R^(9a) is chlorine, R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 16

Compounds of the formula I.1 in which R^(9a) and R^(9d) are chlorine, R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 17

Compounds of the formula I.1 in which R^(9a) and R^(9c) form together a group —CH₂—, R^(8a), R^(8b), R^(8C), R^(8d), R^(9b), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 18

Compounds of the formula I.1 in which R^(8a) and R^(9a) are methyl R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 19

Compounds of the formula I.1 in which R^(8b) and R^(9b) are methyl R^(8a), R^(8c), R^(8d), R^(9a), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 20

Compounds of the formula I.1 in which R^(10a) is methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 21

Compounds of the formula I.1 in which R^(10b) is methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 22

Compounds of the formula I.1 in which R^(10a) and R^(10b) are methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 23

Compounds of the formula I.1 in which R^(10b) and R^(10c) are methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 24

Compounds of the formula I.1 in which R^(10a), R^(10b) and R^(10c) are methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 25

Compounds of the formula I.1 in which R^(10a), R^(10b) and R^(10d) are methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d) and R^(10c) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 26

Compounds of the formula I.1 in which R^(8a), R^(9a) and R^(10a) are methyl R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 27

Compounds of the formula I.1 in which R^(10a) is fluorine, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 28

Compounds of the formula I.1 in which R^(10b) is fluorine, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 29

Compounds of the formula I.1 in which R^(10a) is chlorine, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 30

Compounds of the formula I.1 in which R^(10b) is chlorine, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 31

Compounds of the formula I.2 in which R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 32

Compounds of the formula I.2 in which R^(8a) is methyl, R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 33

Compounds of the formula I.2 in which R^(8b) is methyl, R^(8a), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 34

Compounds of the formula I.2 in which R^(8a) and R^(8b) are methyl, R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 35

Compounds of the formula I.2 in which R^(8a) and R^(8c) are methyl, R^(8b), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 36

Compounds of the formula I.2 in which R^(8a) and R^(8d) are methyl, R^(8b), R^(8c), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 37

Compounds of the formula I.2 in which R^(8b) is fluorine, R^(8a), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 38

Compounds of the formula I.2 in which R^(8b) and R^(8c) are fluorine, R^(8a), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 39

Compounds of the formula I.2 in which R^(8b) is chlorine, R^(8a), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 40

Compounds of the formula I.2 in which R^(8b) and R^(8c) are chlorine, R^(8a), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 41

Compounds of the formula I.2 in which R^(8a) and R^(8c) form together a group —CH₂—, R^(8b), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 42

Compounds of the formula I.2 in which R^(9a) is methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 43

Compounds of the formula I.2 in which R^(9b) is methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 44

Compounds of the formula I.2 in which R^(9a) and R^(9b) are methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 45

Compounds of the formula I.2 in which R^(9a) and R^(9c) are methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 46

Compounds of the formula I.2 in which R^(9a) and R^(9d) are methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 47

Compounds of the formula I.2 in which R^(9a) and R^(9c) form together a group —CH₂—, R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 48

Compounds of the formula I.2 in which R^(8a) and R^(9a) are methyl R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 49

Compounds of the formula I.2 in which R^(8b) and R^(9b) are methyl R^(8a), R^(8c), R^(8d), R^(9a), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 50

Compounds of the formula I.2 in which R^(10a) is methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 51

Compounds of the formula I.2 in which R^(10b) is methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 52

Compounds of the formula I.2 in which R^(10a) and R^(10b) are methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 53

Compounds of the formula I.2 in which R^(10b) and R^(10c) are methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 54

Compounds of the formula I.2 in which R^(10a), R^(10b) and R^(10c) are methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 55

Compounds of the formula I.2 in which R^(10a), R^(10b) and R^(10d) are methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d) and R^(10c) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 56

Compounds of the formula I.2 in which R^(8a), R^(9a) and R^(10a) are methyl R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 57

Compounds of the formula I.2 in which R^(10a) is fluorine, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 58

Compounds of the formula I.2 in which R^(10b) is fluorine, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 59

Compounds of the formula I.2 in which R^(10a) is chlorine, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 60

Compounds of the formula I.2 in which R^(10b) is chlorine, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 61

Compounds of the formula I.3 in which R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 62

Compounds of the formula I.3 in which R^(8a) is methyl, R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 63

Compounds of the formula I.3 in which R^(8b) is methyl, R^(8a), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 64

Compounds of the formula I.3 in which R^(8a) and R^(8b) are methyl, R^(8b), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 65

Compounds of the formula I.3 in which R^(8a) and R^(8b) are methyl, R^(8b), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 66

Compounds of the formula I.3 in which R^(8a) and R^(8d) are methyl, R^(8b), R^(8c), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 67

Compounds of the formula I.3 in which R^(8b) is fluorine, R^(8a), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 68

Compounds of the formula I.3 in which R^(8b) and R^(8c) are fluorine, R^(8a), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 69

Compounds of the formula I.3 in which R^(8b) is chlorine, R^(8a), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 70

Compounds of the formula I.3 in which R^(8b) and R^(8c) are chlorine, R^(8a), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 71

Compounds of the formula I.3 in which R^(8a) and R^(8c) form together a group —CH₂—, R^(8b), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 72

Compounds of the formula I.3 in which R^(9a) is methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 73

Compounds of the formula I.3 in which R^(9b) is methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 74

Compounds of the formula I.3 in which R^(9a) and R^(9b) are methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 75

Compounds of the formula I.3 in which R^(9a) and R^(9c) are methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 76

Compounds of the formula I.3 in which R^(9a) and R^(9d) are methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 77

Compounds of the formula I.3 in which R^(9a) is fluorine, R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 78

Compounds of the formula I.3 in which R^(9a) and R^(9d) are fluorine, R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 79

Compounds of the formula I.3 in which R^(9a) is chlorine, R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 80

Compounds of the formula I.3 in which R^(9a) and R^(9d) are chlorine, R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9c), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 81

Compounds of the formula I.3 in which R^(9a) and R^(9c) form together a group —CH₂—, R^(8a), R^(8b), R^(8c), R^(8d), R^(9b), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 82

Compounds of the formula I.3 in which R^(10a) is methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 83

Compounds of the formula I.3 in which R^(10b) is methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 84

Compounds of the formula I.3 in which R^(10a) and R^(10b) are methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 85

Compounds of the formula I.3 in which R^(10b) and R^(10c) are methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 86

Compounds of the formula I.3 in which R^(10a), R^(10b) and R^(10c) are methyl, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 87

Compounds of the formula I.3 in which R^(10a) is fluorine, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 88

Compounds of the formula I.3 in which R^(10b) is fluorine, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 89

Compounds of the formula I.3 in which R^(10a) is chlorine, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10b), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Table 90

Compounds of the formula I.3 in which R^(10b) is chlorine, R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10c) and R^(10d) are hydrogen, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 91 to 120

Compounds of the formula I.4 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 121 to 150

Compounds of the formula I.5 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 151 to 180

Compounds of the formula I.6 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 181 to 210

Compounds of the formula I.7 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 211 to 240

Compounds of the formula I.8 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 241 to 270

Compounds of the formula I.9 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 271 to 300

Compounds of the formula I.10 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 301 to 330

Compounds of the formula I.11 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 331 to 360

Compounds of the formula I.12 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 361 to 390

Compounds of the formula I.13 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 391 to 420

Compounds of the formula I.14 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 421 to 450

Compounds of the formula I.15 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 451 to 480

Compounds of the formula I.16 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 481 to 510

Compounds of the formula I.17 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 511 to 540

Compounds of the formula I.18 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 541 to 570

Compounds of the formula I.19 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 571 to 600

Compounds of the formula I.20 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 601 to 630

Compounds of the formula I.21 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 631 to 660

Compounds of the formula I.22 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 661 to 690

Compounds of the formula I.23 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 691 to 720

Compounds of the formula I.24 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 721 to 750

Compounds of the formula I.25 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 751 to 780

Compounds of the formula I.26 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 781 to 810

Compounds of the formula I.27 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 811 to 840

Compounds of the formula I.28 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 841 to 870

Compounds of the formula I.29 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 871 to 900

Compounds of the formula I.30 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 901 to 930

Compounds of the formula I.31 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 931 to 960

Compounds of the formula I.32 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 961 to 990

Compounds of the formula I.33 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 991 to 1020

Compounds of the formula I.34 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 1021 to 1050

Compounds of the formula I.35 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 1051 to 1080

Compounds of the formula I.36 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 1081 to 1110

Compounds of the formula I.37 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 1111 to 1140

Compounds of the formula I.38 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 1141 to 1170

Compounds of the formula I.39 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 1171 to 1200

Compounds of the formula I.40 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 1201 to 1230

Compounds of the formula I.41 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 1231 to 1260

Compounds of the formula I.42 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 1261 to 1290

Compounds of the formula I.43 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 1291 to 1320

Compounds of the formula I.44 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 1321 to 1350

Compounds of the formula I.45 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 1351 to 1380

Compounds of the formula I.46 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 1381 to 1410

Compounds of the formula I.47 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 1411 to 1440

Compounds of the formula I.48 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 1441 to 1470

Compounds of the formula I.49 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 1471 to 1500

Compounds of the formula I.50 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 1501 to 1530

Compounds of the formula I.51 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 1531 to 1560

Compounds of the formula I.52 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 1561 to 1590

Compounds of the formula I.53 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 1591 to 1620

Compounds of the formula I.54 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 1621 to 1650

Compounds of the formula I.55 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 1651 to 1680

Compounds of the formula I.56 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 1681 to 1710

Compounds of the formula I.57 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 1711 to 1740

Compounds of the formula I.58 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 1741 to 1770

Compounds of the formula I.59 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 1771 to 1800

Compounds of the formula I.60 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 1801 to 1830

Compounds of the formula I.61 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 1831 to 1860

Compounds of the formula I.62 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 1861 to 1890

Compounds of the formula I.63 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 1891 to 1920

Compounds of the formula I.64 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 1921 to 1950

Compounds of the formula I.65 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 1951 to 1980

Compounds of the formula I.66 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 1981 to 2010

Compounds of the formula I.67 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 2011 to 2040

Compounds of the formula I.68 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 2041 to 2070

Compounds of the formula I.69 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 2071 to 2100

Compounds of the formula I.70 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 2101 to 2130

Compounds of the formula I.71 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 2131 to 2160

Compounds of the formula I.72 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 2161 to 2190

Compounds of the formula I.73 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 2191 to 2220

Compounds of the formula I.74 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 2221 to 2250

Compounds of the formula I.75 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 2251 to 2280

Compounds of the formula I.76 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 2281 to 2310

Compounds of the formula I.77 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 2311 to 2340

Compounds of the formula I.78 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 2341 to 2370

Compounds of the formula I.79 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 2370 to 2400

Compounds of the formula I.80 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 2401 to 2430

Compounds of the formula I.81 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R¹, R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table A

Tables 2431 to 2460

Compounds of the formula I.82 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 1 to 30, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 2461 to 2490

Compounds of the formula I.83 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 31 to 60, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

Tables 2491 to 2520

Compounds of the formula I.84 in which the combination of R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b), R^(10c) and R^(10d) is as defined in any of Tables 61 to 90, and R², R³, R⁶ and R⁷ for a compound corresponds in each case to one row of Table B

TABLE A Example No. R¹ R² R³ R⁶ R⁷ A-1. H H H CN H A-2. F H H CN H A-3. CH₃ H H CN H A-4. OCH₃ H H CN H A-5. CH₂F H H CN H A-6. CHF₂ H H CN H A-7. CF₃ H H CN H A-8. OCH₂F H H CN H A-9. OCHF₂ H H CN H A-10. OCF₃ H H CN H A-11. H F H CN H A-12. H CH₃ H CN H A-13. H OCH₃ H CN H A-14. H CN H CN H A-15. H CH₂F H CN H A-16. H CHF₂ H CN H A-17. H CF₃ H CN H A-18. H OCH₂F H CN H A-19. H OCHF₂ H CN H A-20. H OCF₃ H CN H A-21. H H 3-F CN H A-22. H H 3-CH₃ CN H A-23. H H 3-OCH₃ CN H A-24. H H 5-F CN H A-25. H H 5-CH₃ CN H A-26. H H 5-OCH₃ CN H A-27. F F H CN H A-28. F CH₃ H CN H A-29. F OCH₃ H CN H A-30. F CN H CN H A-31. F CH₂F H CN H A-32. F CHF₂ H CN H A-33. F CF₃ H CN H A-34. F OCH₂F H CN H A-35. F OCHF₂ H CN H A-36. F OCF₃ H CN H A-37. F H 3-F CN H A-38. F H 3-CH₃ CN H A-39. F H 3-OCH₃ CN H A-40. F H 5-F CN H A-41. F H 5-CH₃ CN H A-42. F H 5-OCH₃ CN H A-43. CH₃ F H CN H A-44. CH₃ CH₃ H CN H A-45. CH₃ OCH₃ H CN H A-46. CH₃ CN H CN H A-47. CH₃ CH₂F H CN H A-48. CH₃ CHF₂ H CN H A-49. CH₃ CF₃ H CN H A-50. CH₃ OCH₂F H CN H A-51. CH₃ OCHF₂ H CN H A-52. CH₃ OCF₃ H CN H A-53. CH₃ H 3-F CN H A-54. CH₃ H 3-CH₃ CN H A-55. CH₃ H 3-OCH₃ CN H A-56. CH₃ H 5-F CN H A-57. CH₃ H 5-CH₃ CN H A-58. CH₃ H 5-OCH₃ CN H A-59. OCH₃ F H CN H A-60. OCH₃ CH₃ H CN H A-61. OCH₃ OCH₃ H CN H A-62. OCH₃ CN H CN H A-63. OCH₃ CH₂F H CN H A-64. OCH₃ CHF₂ H CN H A-65. OCH₃ CF₃ H CN H A-66. OCH₃ OCH₂F H CN H A-67. OCH₃ OCHF₂ H CN H A-68. OCH₃ OCF₃ H CN H A-69. OCH₃ H 3-F CN H A-70. OCH₃ H 3-CH₃ CN H A-71. OCH₃ H 3-OCH₃ CN H A-72. OCH₃ H 5-F CN H A-73. OCH₃ H 5-CH₃ CN H A-74. OCH₃ H 5-OCH₃ CN H A-75. H F 3-F CN H A-76. H F 3-CH₃ CN H A-77. H F 3-OCH₃ CN H A-78. H F 5-F CN H A-79. H F 5-CH₃ CN H A-80. H F 5-OCH₃ CN H A-81. H CH₃ 3-F CN H A-82. H CH₃ 3-CH₃ CN H A-83. H CH₃ 3-OCH₃ CN H A-84. H CH₃ 5-F CN H A-85. H CH₃ 5-CH₃ CN H A-86. H CH₃ 5-OCH₃ CN H A-87. H OCH₃ 3-F CN H A-88. H OCH₃ 3-CH₃ CN H A-89. H OCH₃ 3-OCH₃ CN H A-90. H OCH₃ 5-F CN H A-91. H OCH₃ 5-CH₃ CN H A-92. H OCH₃ 5-OCH₃ CN H A-93. H CN 3-F CN H A-94. H CN 3-CH₃ CN H A-95. H CN 3-OCH₃ CN H A-96. H CN 5-F CN H A-97. H CN 5-CH₃ CN H A-98. H CN 5-OCH₃ CN H A-99. H CH₂F 3-F CN H A-100. H CH₂F 3-CH₃ CN H A-101. H CH₂F 3-OCH₃ CN H A-102. H CH₂F 5-F CN H A-103. H CH₂F 5-CH₃ CN H A-104. H CH₂F 5-OCH₃ CN H A-105. H CHF₂ 3-F CN H A-106. H CHF₂ 3-CH₃ CN H A-107. H CHF₂ 3-OCH₃ CN H A-108. H CHF₂ 5-F CN H A-109. H CHF₂ 5-CH₃ CN H A-110. H CHF₂ 5-OCH₃ CN H A-111. H CF₃ 3-F CN H A-112. H CF₃ 3-CH₃ CN H A-113. H CF₃ 3-OCH₃ CN H A-114. H CF₃ 5-F CN H A-115. H CF₃ 5-CH₃ CN H A-116. H CF₃ 5-OCH₃ CN H A-117. H OCH₂F 3-F CN H A-118. H OCH₂F 3-CH₃ CN H A-119. H OCH₂F 3-OCH₃ CN H A-120. H OCH₂F 5-F CN H A-121. H OCH₂F 5-CH₃ CN H A-122. H OCH₂F 5-OCH₃ CN H A-123. H OCHF₂ 3-F CN H A-124. H OCHF₂ 3-CH₃ CN H A-125. H OCHF₂ 3-OCH₃ CN H A-126. H OCHF₂ 5-F CN H A-127. H OCHF₂ 5-CH₃ CN H A-128. H OCHF₂ 5-OCH₃ CN H A-129. H OCF₃ 3-F CN H A-130. H OCF₃ 3-CH₃ CN H A-131. H OCF₃ 3-OCH₃ CN H A-132. H OCF₃ 5-F CN H A-133. H OCF₃ 5-CH₃ CN H A-134. H OCF₃ 5-OCH₃ CN H A-135. F F 3-F CN H A-136. F F 3-CH₃ CN H A-137. F F 3-OCH₃ CN H A-138. F F 5-F CN H A-139. F F 5-CH₃ CN H A-140. F F 5-OCH₃ CN H A-141. F CH₃ 3-F CN H A-142. F CH₃ 3-CH₃ CN H A-143. F CH₃ 3-OCH₃ CN H A-144. F CH₃ 5-F CN H A-145. F CH₃ 5-CH₃ CN H A-146. F CH₃ 5-OCH₃ CN H A-147. F OCH₃ 3-F CN H A-148. F OCH₃ 3-CH₃ CN H A-149. F OCH₃ 3-OCH₃ CN H A-150. F OCH₃ 5-F CN H A-151. F OCH₃ 5-CH₃ CN H A-152. F OCH₃ 5-OCH₃ CN H A-153. F CN 3-F CN H A-154. F CN 3-CH₃ CN H A-155. F CN 3-OCH₃ CN H A-156. F CN 5-F CN H A-157. F CN 5-CH₃ CN H A-158. F CN 5-OCH₃ CN H A-159. F CH₂F 3-F CN H A-160. F CH₂F 3-CH₃ CN H A-161. F CH₂F 3-OCH₃ CN H A-162. F CH₂F 5-F CN H A-163. F CH₂F 5-CH₃ CN H A-164. F CH₂F 5-OCH₃ CN H A-165. F CHF₂ 3-F CN H A-166. F CHF₂ 3-CH₃ CN H A-167. F CHF₂ 3-OCH₃ CN H A-168. F CHF₂ 5-F CN H A-169. F CHF₂ 5-CH₃ CN H A-170. F CHF₂ 5-OCH₃ CN H A-171. F CF₃ 3-F CN H A-172. F CF₃ 3-CH₃ CN H A-173. F CF₃ 3-OCH₃ CN H A-174. F CF₃ 5-F CN H A-175. F CF₃ 5-CH₃ CN H A-176. F CF₃ 5-OCH₃ CN H A-177. F OCH₂F 3-F CN H A-178. F OCH₂F 3-CH₃ CN H A-179. F OCH₂F 3-OCH₃ CN H A-180. F OCH₂F 5-F CN H A-181. F OCH₂F 5-CH₃ CN H A-182. F OCH₂F 5-OCH₃ CN H A-183. F OCHF₂ 3-F CN H A-184. F OCHF₂ 3-CH₃ CN H A-185. F OCHF₂ 3-OCH₃ CN H A-186. F OCHF₂ 5-F CN H A-187. F OCHF₂ 5-CH₃ CN H A-188. F OCHF₂ 5-OCH₃ CN H A-189. F OCF₃ 3-F CN H A-190. F OCF₃ 3-CH₃ CN H A-191. F OCF₃ 3-OCH₃ CN H A-192. F OCF₃ 5-F CN H A-193. F OCF₃ 5-CH₃ CN H A-194. F OCF₃ 5-OCH₃ CN H A-195. CH₃ F 3-F CN H A-196. CH₃ F 3-CH₃ CN H A-197. CH₃ F 3-OCH₃ CN H A-198. CH₃ F 5-F CN H A-199. CH₃ F 5-CH₃ CN H A-200. CH₃ F 5-OCH₃ CN H A-201. CH₃ CH₃ 3-F CN H A-202. CH₃ CH₃ 3-CH₃ CN H A-203. CH₃ CH₃ 3-OCH₃ CN H A-204. CH₃ CH₃ 5-F CN H A-205. CH₃ CH₃ 5-CH₃ CN H A-206. CH₃ CH₃ 5-OCH₃ CN H A-207. CH₃ OCH₃ 3-F CN H A-208. CH₃ OCH₃ 3-CH₃ CN H A-209. CH₃ OCH₃ 3-OCH₃ CN H A-210. CH₃ OCH₃ 5-F CN H A-211. CH₃ OCH₃ 5-CH₃ CN H A-212. CH₃ OCH₃ 5-OCH₃ CN H A-213. CH₃ CN 3-F CN H A-214. CH₃ CN 3-CH₃ CN H A-215. CH₃ CN 3-OCH₃ CN H A-216. CH₃ CN 5-F CN H A-217. CH₃ CN 5-CH₃ CN H A-218. CH₃ CN 5-OCH₃ CN H A-219. CH₃ CH₂F 3-F CN H A-220. CH₃ CH₂F 3-CH₃ CN H A-221. CH₃ CH₂F 3-OCH₃ CN H A-222. CH₃ CH₂F 5-F CN H A-223. CH₃ CH₂F 5-CH₃ CN H A-224. CH₃ CH₂F 5-OCH₃ CN H A-225. CH₃ CHF₂ 3-F CN H A-226. CH₃ CHF₂ 3-CH₃ CN H A-227. CH₃ CHF₂ 3-OCH₃ CN H A-228. CH₃ CHF₂ 5-F CN H A-229. CH₃ CHF₂ 5-CH₃ CN H A-230. CH₃ CHF₂ 5-OCH₃ CN H A-231. CH₃ CF₃ 3-F CN H A-232. CH₃ CF₃ 3-CH₃ CN H A-233. CH₃ CF₃ 3-OCH₃ CN H A-234. CH₃ CF₃ 5-F CN H A-235. CH₃ CF₃ 5-CH₃ CN H A-236. CH₃ CF₃ 5-OCH₃ CN H A-237. CH₃ OCH₂F 3-F CN H A-238. CH₃ OCH₂F 3-CH₃ CN H A-239. CH₃ OCH₂F 3-OCH₃ CN H A-240. CH₃ OCH₂F 5-F CN H A-241. CH₃ OCH₂F 5-CH₃ CN H A-242. CH₃ OCH₂F 5-OCH₃ CN H A-243. CH₃ OCHF₂ 3-F CN H A-244. CH₃ OCHF₂ 3-CH₃ CN H A-245. CH₃ OCHF₂ 3-OCH₃ CN H A-246. CH₃ OCHF₂ 5-F CN H A-247. CH₃ OCHF₂ 5-CH₃ CN H A-248. CH₃ OCHF₂ 5-OCH₃ CN H A-249. CH₃ OCF₃ 3-F CN H A-250. CH₃ OCF₃ 3-CH₃ CN H A-251. CH₃ OCF₃ 3-OCH₃ CN H A-252. CH₃ OCF₃ 5-F CN H A-253. CH₃ OCF₃ 5-CH₃ CN H A-254. CH₃ OCF₃ 5-OCH₃ CN H A-255. OCH₃ F 3-F CN H A-256. OCH₃ F 3-CH₃ CN H A-257. OCH₃ F 3-OCH₃ CN H A-258. OCH₃ F 5-F CN H A-259. OCH₃ F 5-CH₃ CN H A-260. OCH₃ F 5-OCH₃ CN H A-261. OCH₃ CH₃ 3-F CN H A-262. OCH₃ CH₃ 3-CH₃ CN H A-263. OCH₃ CH₃ 3-OCH₃ CN H A-264. OCH₃ CH₃ 5-F CN H A-265. OCH₃ CH₃ 5-CH₃ CN H A-266. OCH₃ CH₃ 5-OCH₃ CN H A-267. OCH₃ OCH₃ 3-F CN H A-268. OCH₃ OCH₃ 3-CH₃ CN H A-269. OCH₃ OCH₃ 3-OCH₃ CN H A-270. OCH₃ OCH₃ 5-F CN H A-271. OCH₃ OCH₃ 5-CH₃ CN H A-272. OCH₃ OCH₃ 5-OCH₃ CN H A-273. OCH₃ CN 3-F CN H A-274. OCH₃ CN 3-CH₃ CN H A-275. OCH₃ CN 3-OCH₃ CN H A-276. OCH₃ CN 5-F CN H A-277. OCH₃ CN 5-CH₃ CN H A-278. OCH₃ CN 5-OCH₃ CN H A-279. OCH₃ CH₂F 3-F CN H A-280. OCH₃ CH₂F 3-CH₃ CN H A-281. OCH₃ CH₂F 3-OCH₃ CN H A-282. OCH₃ CH₂F 5-F CN H A-283. OCH₃ CH₂F 5-CH₃ CN H A-284. OCH₃ CH₂F 5-OCH₃ CN H A-285. OCH₃ CHF₂ 3-F CN H A-286. OCH₃ CHF₂ 3-CH₃ CN H A-287. OCH₃ CHF₂ 3-OCH₃ CN H A-288. OCH₃ CHF₂ 5-F CN H A-289. OCH₃ CHF₂ 5-CH₃ CN H A-290. OCH₃ CHF₂ 5-OCH₃ CN H A-291. OCH₃ CF₃ 3-F CN H A-292. OCH₃ CF₃ 3-CH₃ CN H A-293. OCH₃ CF₃ 3-OCH₃ CN H A-294. OCH₃ CF₃ 5-F CN H A-295. OCH₃ CF₃ 5-CH₃ CN H A-296. OCH₃ CF₃ 5-OCH₃ CN H A-297. OCH₃ OCH₂F 3-F CN H A-298. OCH₃ OCH₂F 3-CH₃ CN H A-299. OCH₃ OCH₂F 3-OCH₃ CN H A-300. OCH₃ OCH₂F 5-F CN H A-301. OCH₃ OCH₂F 5-CH₃ CN H A-302. OCH₃ OCH₂F 5-OCH₃ CN H A-303. OCH₃ OCHF₂ 3-F CN H A-304. OCH₃ OCHF₂ 3-CH₃ CN H A-305. OCH₃ OCHF₂ 3-OCH₃ CN H A-306. OCH₃ OCHF₂ 5-F CN H A-307. OCH₃ OCHF₂ 5-CH₃ CN H A-308. OCH₃ OCHF₂ 5-OCH₃ CN H A-309. OCH₃ OCF₃ 3-F CN H A-310. OCH₃ OCF₃ 3-CH₃ CN H A-311. OCH₃ OCF₃ 3-OCH₃ CN H A-312. OCH₃ OCF₃ 5-F CN H A-313. OCH₃ OCF₃ 5-CH₃ CN H A-314. OCH₃ OCF₃ 5-OCH₃ CN H A-315. CH₂F F 3-F CN H A-316. CH₂F F 3-CH₃ CN H A-317. CH₂F F 3-OCH₃ CN H A-318. CH₂F F 5-F CN H A-319. CH₂F F 5-CH₃ CN H A-320. CH₂F F 5-OCH₃ CN H A-321. CH₂F CH₃ 3-F CN H A-322. CH₂F CH₃ 3-CH₃ CN H A-323. CH₂F CH₃ 3-OCH₃ CN H A-324. CH₂F CH₃ 5-F CN H A-325. CH₂F CH₃ 5-CH₃ CN H A-326. CH₂F CH₃ 5-OCH₃ CN H A-327. CH₂F OCH₃ 3-F CN H A-328. CH₂F OCH₃ 3-CH₃ CN H A-329. CH₂F OCH₃ 3-OCH₃ CN H A-330. CH₂F OCH₃ 5-F CN H A-331. CH₂F OCH₃ 5-CH₃ CN H A-332. CH₂F OCH₃ 5-OCH₃ CN H A-333. CH₂F CN 3-F CN H A-334. CH₂F CN 3-CH₃ CN H A-335. CH₂F CN 3-OCH₃ CN H A-336. CH₂F CN 5-F CN H A-337. CH₂F CN 5-CH₃ CN H A-338. CH₂F CN 5-OCH₃ CN H A-339. CH₂F CH₂F 3-F CN H A-340. CH₂F CH₂F 3-CH₃ CN H A-341. CH₂F CH₂F 3-OCH₃ CN H A-342. CH₂F CH₂F 5-F CN H A-343. CH₂F CH₂F 5-CH₃ CN H A-344. CH₂F CH₂F 5-OCH₃ CN H A-345. CH₂F CHF₂ 3-F CN H A-346. CH₂F CHF₂ 3-CH₃ CN H A-347. CH₂F CHF₂ 3-OCH₃ CN H A-348. CH₂F CHF₂ 5-F CN H A-349. CH₂F CHF₂ 5-CH₃ CN H A-350. CH₂F CHF₂ 5-OCH₃ CN H A-351. CH₂F CF₃ 3-F CN H A-352. CH₂F CF₃ 3-CH₃ CN H A-353. CH₂F CF₃ 3-OCH₃ CN H A-354. CH₂F CF₃ 5-F CN H A-355. CH₂F CF₃ 5-CH₃ CN H A-356. CH₂F CF₃ 5-OCH₃ CN H A-357. CH₂F OCH₂F 3-F CN H A-358. CH₂F OCH₂F 3-CH₃ CN H A-359. CH₂F OCH₂F 3-OCH₃ CN H A-360. CH₂F OCH₂F 5-F CN H A-361. CH₂F OCH₂F 5-CH₃ CN H A-362. CH₂F OCH₂F 5-OCH₃ CN H A-363. CH₂F OCHF₂ 3-F CN H A-364. CH₂F OCHF₂ 3-CH₃ CN H A-365. CH₂F OCHF₂ 3-OCH₃ CN H A-366. CH₂F OCHF₂ 5-F CN H A-367. CH₂F OCHF₂ 5-CH₃ CN H A-368. CH₂F OCHF₂ 5-OCH₃ CN H A-369. CH₂F OCF₃ 3-F CN H A-370. CH₂F OCF₃ 3-CH₃ CN H A-371. CH₂F OCF₃ 3-OCH₃ CN H A-372. CH₂F OCF₃ 5-F CN H A-373. CH₂F OCF₃ 5-CH₃ CN H A-374. CH₂F OCF₃ 5-OCH₃ CN H A-375. CHF₂ F 3-F CN H A-376. CHF₂ F 3-CH₃ CN H A-377. CHF₂ F 3-OCH₃ CN H A-378. CHF₂ F 5-F CN H A-379. CHF₂ F 5-CH₃ CN H A-380. CHF₂ F 5-OCH₃ CN H A-381. CHF₂ CH₃ 3-F CN H A-382. CHF₂ CH₃ 3-CH₃ CN H A-383. CHF₂ CH₃ 3-OCH₃ CN H A-384. CHF₂ CH₃ 5-F CN H A-385. CHF₂ CH₃ 5-CH₃ CN H A-386. CHF₂ CH₃ 5-OCH₃ CN H A-387. CHF₂ OCH₃ 3-F CN H A-388. CHF₂ OCH₃ 3-CH₃ CN H A-389. CHF₂ OCH₃ 3-OCH₃ CN H A-390. CHF₂ OCH₃ 5-F CN H A-391. CHF₂ OCH₃ 5-CH₃ CN H A-392. CHF₂ OCH₃ 5-OCH₃ CN H A-393. CHF₂ CN 3-F CN H A-394. CHF₂ CN 3-CH₃ CN H A-395. CHF₂ CN 3-OCH₃ CN H A-396. CHF₂ CN 5-F CN H A-397. CHF₂ CN 5-CH₃ CN H A-398. CHF₂ CN 5-OCH₃ CN H A-399. CHF₂ CH₂F 3-F CN H A-400. CHF₂ CH₂F 3-CH₃ CN H A-401. CHF₂ CH₂F 3-OCH₃ CN H A-402. CHF₂ CH₂F 5-F CN H A-403. CHF₂ CH₂F 5-CH₃ CN H A-404. CHF₂ CH₂F 5-OCH₃ CN H A-405. CHF₂ CHF₂ 3-F CN H A-406. CHF₂ CHF₂ 3-CH₃ CN H A-407. CHF₂ CHF₂ 3-OCH₃ CN H A-408. CHF₂ CHF₂ 5-F CN H A-409. CHF₂ CHF₂ 5-CH₃ CN H A-410. CHF₂ CHF₂ 5-OCH₃ CN H A-411. CHF₂ CF₃ 3-F CN H A-412. CHF₂ CF₃ 3-CH₃ CN H A-413. CHF₂ CF₃ 3-OCH₃ CN H A-414. CHF₂ CF₃ 5-F CN H A-415. CHF₂ CF₃ 5-CH₃ CN H A-416. CHF₂ CF₃ 5-OCH₃ CN H A-417. CHF₂ OCH₂F 3-F CN H A-418. CHF₂ OCH₂F 3-CH₃ CN H A-419. CHF₂ OCH₂F 3-OCH₃ CN H A-420. CHF₂ OCH₂F 5-F CN H A-421. CHF₂ OCH₂F 5-CH₃ CN H A-422. CHF₂ OCH₂F 5-OCH₃ CN H A-423. CHF₂ OCHF₂ 3-F CN H A-424. CHF₂ OCHF₂ 3-CH₃ CN H A-425. CHF₂ OCHF₂ 3-OCH₃ CN H A-426. CHF₂ OCHF₂ 5-F CN H A-427. CHF₂ OCHF₂ 5-CH₃ CN H A-428. CHF₂ OCHF₂ 5-OCH₃ CN H A-429. CHF₂ OCF₃ 3-F CN H A-430. CHF₂ OCF₃ 3-CH₃ CN H A-431. CHF₂ OCF₃ 3-OCH₃ CN H A-432. CHF₂ OCF₃ 5-F CN H A-433. CHF₂ OCF₃ 5-CH₃ CN H A-434. CHF₂ OCF₃ 5-OCH₃ CN H A-435. CF₃ F 3-F CN H A-436. CF₃ F 3-CH₃ CN H A-437. CF₃ F 3-OCH₃ CN H A-438. CF₃ F 5-F CN H A-439. CF₃ F 5-CH₃ CN H A-440. CF₃ F 5-OCH₃ CN H A-441. CF₃ CH₃ 3-F CN H A-442. CF₃ CH₃ 3-CH₃ CN H A-443. CF₃ CH₃ 3-OCH₃ CN H A-444. CF₃ CH₃ 5-F CN H A-445. CF₃ CH₃ 5-CH₃ CN H A-446. CF₃ CH₃ 5-OCH₃ CN H A-447. CF₃ OCH₃ 3-F CN H A-448. CF₃ OCH₃ 3-CH₃ CN H A-449. CF₃ OCH₃ 3-OCH₃ CN H A-450. CF₃ OCH₃ 5-F CN H A-451. CF₃ OCH₃ 5-CH₃ CN H A-452. CF₃ OCH₃ 5-OCH₃ CN H A-453. CF₃ CN 3-F CN H A-454. CF₃ CN 3-CH₃ CN H A-455. CF₃ CN 3-OCH₃ CN H A-456. CF₃ CN 5-F CN H A-457. CF₃ CN 5-CH₃ CN H A-458. CF₃ CN 5-OCH₃ CN H A-459. CF₃ CH₂F 3-F CN H A-460. CF₃ CH₂F 3-CH₃ CN H A-461. CF₃ CH₂F 3-OCH₃ CN H A-462. CF₃ CH₂F 5-F CN H A-463. CF₃ CH₂F 5-CH₃ CN H A-464. CF₃ CH₂F 5-OCH₃ CN H A-465. CF₃ CHF₂ 3-F CN H A-466. CF₃ CHF₂ 3-CH₃ CN H A-467. CF₃ CHF₂ 3-OCH₃ CN H A-468. CF₃ CHF₂ 5-F CN H A-469. CF₃ CHF₂ 5-CH₃ CN H A-470. CF₃ CHF₂ 5-OCH₃ CN H A-471. CF₃ CF₃ 3-F CN H A-472. CF₃ CF₃ 3-CH₃ CN H A-473. CF₃ CF₃ 3-OCH₃ CN H A-474. CF₃ CF₃ 5-F CN H A-475. CF₃ CF₃ 5-CH₃ CN H A-476. CF₃ CF₃ 5-OCH₃ CN H A-477. CF₃ OCH₂F 3-F CN H A-478. CF₃ OCH₂F 3-CH₃ CN H A-479. CF₃ OCH₂F 3-OCH₃ CN H A-480. CF₃ OCH₂F 5-F CN H A-481. CF₃ OCH₂F 5-CH₃ CN H A-482. CF₃ OCH₂F 5-OCH₃ CN H A-483. CF₃ OCHF₂ 3-F CN H A-484. CF₃ OCHF₂ 3-CH₃ CN H A-485. CF₃ OCHF₂ 3-OCH₃ CN H A-486. CF₃ OCHF₂ 5-F CN H A-487. CF₃ OCHF₂ 5-CH₃ CN H A-488. CF₃ OCHF₂ 5-OCH₃ CN H A-489. CF₃ OCF₃ 3-F CN H A-490. CF₃ OCF₃ 3-CH₃ CN H A-491. CF₃ OCF₃ 3-OCH₃ CN H A-492. CF₃ OCF₃ 5-F CN H A-493. CF₃ OCF₃ 5-CH₃ CN H A-494. CF₃ OCF₃ 5-OCH₃ CN H A-495. OCH₂F F 3-F CN H A-496. OCH₂F F 3-CH₃ CN H A-497. OCH₂F F 3-OCH₃ CN H A-498. OCH₂F F 5-F CN H A-499. OCH₂F F 5-CH₃ CN H A-500. OCH₂F F 5-OCH₃ CN H A-501. OCH₂F CH₃ 3-F CN H A-502. OCH₂F CH₃ 3-CH₃ CN H A-503. OCH₂F CH₃ 3-OCH₃ CN H A-504. OCH₂F CH₃ 5-F CN H A-505. OCH₂F CH₃ 5-CH₃ CN H A-506. OCH₂F CH₃ 5-OCH₃ CN H A-507. OCH₂F OCH₃ 3-F CN H A-508. OCH₂F OCH₃ 3-CH₃ CN H A-509. OCH₂F OCH₃ 3-OCH₃ CN H A-510. OCH₂F OCH₃ 5-F CN H A-511. OCH₂F OCH₃ 5-CH₃ CN H A-512. OCH₂F OCH₃ 5-OCH₃ CN H A-513. OCH₂F CN 3-F CN H A-514. OCH₂F CN 3-CH₃ CN H A-515. OCH₂F CN 3-OCH₃ CN H A-516. OCH₂F CN 5-F CN H A-517. OCH₂F CN 5-CH₃ CN H A-518. OCH₂F CN 5-OCH₃ CN H A-519. OCH₂F CH₂F 3-F CN H A-520. OCH₂F CH₂F 3-CH₃ CN H A-521. OCH₂F CH₂F 3-OCH₃ CN H A-522. OCH₂F CH₂F 5-F CN H A-523. OCH₂F CH₂F 5-CH₃ CN H A-524. OCH₂F CH₂F 5-OCH₃ CN H A-525. OCH₂F CHF₂ 3-F CN H A-526. OCH₂F CHF₂ 3-CH₃ CN H A-527. OCH₂F CHF₂ 3-OCH₃ CN H A-528. OCH₂F CHF₂ 5-F CN H A-529. OCH₂F CHF₂ 5-CH₃ CN H A-530. OCH₂F CHF₂ 5-OCH₃ CN H A-531. OCH₂F CF₃ 3-F CN H A-532. OCH₂F CF₃ 3-CH₃ CN H A-533. OCH₂F CF₃ 3-OCH₃ CN H A-534. OCH₂F CF₃ 5-F CN H A-535. OCH₂F CF₃ 5-CH₃ CN H A-536. OCH₂F CF₃ 5-OCH₃ CN H A-537. OCH₂F OCH₂F 3-F CN H A-538. OCH₂F OCH₂F 3-CH₃ CN H A-539. OCH₂F OCH₂F 3-OCH₃ CN H A-540. OCH₂F OCH₂F 5-F CN H A-541. OCH₂F OCH₂F 5-CH₃ CN H A-542. OCH₂F OCH₂F 5-OCH₃ CN H A-543. OCH₂F OCHF₂ 3-F CN H A-544. OCH₂F OCHF₂ 3-CH₃ CN H A-545. OCH₂F OCHF₂ 3-OCH₃ CN H A-546. OCH₂F OCHF₂ 5-F CN H A-547. OCH₂F OCHF₂ 5-CH₃ CN H A-548. OCH₂F OCHF₂ 5-OCH₃ CN H A-549. OCH₂F OCF₃ 3-F CN H A-550. OCH₂F OCF₃ 3-CH₃ CN H A-551. OCH₂F OCF₃ 3-OCH₃ CN H A-552. OCH₂F OCF₃ 5-F CN H A-553. OCH₂F OCF₃ 5-CH₃ CN H A-554. OCH₂F OCF₃ 5-OCH₃ CN H A-555. OCHF₂ F 3-F CN H A-556. OCHF₂ F 3-CH₃ CN H A-557. OCHF₂ F 3-OCH₃ CN H A-558. OCHF₂ F 5-F CN H A-559. OCHF₂ F 5-CH₃ CN H A-560. OCHF₂ F 5-OCH₃ CN H A-561. OCHF₂ CH₃ 3-F CN H A-562. OCHF₂ CH₃ 3-CH₃ CN H A-563. OCHF₂ CH₃ 3-OCH₃ CN H A-564. OCHF₂ CH₃ 5-F CN H A-565. OCHF₂ CH₃ 5-CH₃ CN H A-566. OCHF₂ CH₃ 5-OCH₃ CN H A-567. OCHF₂ OCH₃ 3-F CN H A-568. OCHF₂ OCH₃ 3-CH₃ CN H A-569. OCHF₂ OCH₃ 3-OCH₃ CN H A-570. OCHF₂ OCH₃ 5-F CN H A-571. OCHF₂ OCH₃ 5-CH₃ CN H A-572. OCHF₂ OCH₃ 5-OCH₃ CN H A-573. OCHF₂ CN 3-F CN H A-574. OCHF₂ CN 3-CH₃ CN H A-575. OCHF₂ CN 3-OCH₃ CN H A-576. OCHF₂ CN 5-F CN H A-577. OCHF₂ CN 5-CH₃ CN H A-578. OCHF₂ CN 5-OCH₃ CN H A-579. OCHF₂ CH₂F 3-F CN H A-580. OCHF₂ CH₂F 3-CH₃ CN H A-581. OCHF₂ CH₂F 3-OCH₃ CN H A-582. OCHF₂ CH₂F 5-F CN H A-583. OCHF₂ CH₂F 5-CH₃ CN H A-584. OCHF₂ CH₂F 5-OCH₃ CN H A-585. OCHF₂ CHF₂ 3-F CN H A-586. OCHF₂ CHF₂ 3-CH₃ CN H A-587. OCHF₂ CHF₂ 3-OCH₃ CN H A-588. OCHF₂ CHF₂ 5-F CN H A-589. OCHF₂ CHF₂ 5-CH₃ CN H A-590. OCHF₂ CHF₂ 5-OCH₃ CN H A-591. OCHF₂ CF₃ 3-F CN H A-592. OCHF₂ CF₃ 3-CH₃ CN H A-593. OCHF₂ CF₃ 3-OCH₃ CN H A-594. OCHF₂ CF₃ 5-F CN H A-595. OCHF₂ CF₃ 5-CH₃ CN H A-596. OCHF₂ CF₃ 5-OCH₃ CN H A-597. OCHF₂ OCH₂F 3-F CN H A-598. OCHF₂ OCH₂F 3-CH₃ CN H A-599. OCHF₂ OCH₂F 3-OCH₃ CN H A-600. OCHF₂ OCH₂F 5-F CN H A-601. OCHF₂ OCH₂F 5-CH₃ CN H A-602. OCHF₂ OCH₂F 5-OCH₃ CN H A-603. OCHF₂ OCHF₂ 3-F CN H A-604. OCHF₂ OCHF₂ 3-CH₃ CN H A-605. OCHF₂ OCHF₂ 3-OCH₃ CN H A-606. OCHF₂ OCHF₂ 5-F CN H A-607. OCHF₂ OCHF₂ 5-CH₃ CN H A-608. OCHF₂ OCHF₂ 5-OCH₃ CN H A-609. OCHF₂ OCF₃ 3-F CN H A-610. OCHF₂ OCF₃ 3-CH₃ CN H A-611. OCHF₂ OCF₃ 3-OCH₃ CN H A-612. OCHF₂ OCF₃ 5-F CN H A-613. OCHF₂ OCF₃ 5-CH₃ CN H A-614. OCHF₂ OCF₃ 5-OCH₃ CN H A-615. OCF₃ F 3-F CN H A-616. OCF₃ F 3-CH₃ CN H A-617. OCF₃ F 3-OCH₃ CN H A-618. OCF₃ F 5-F CN H A-619. OCF₃ F 5-CH₃ CN H A-620. OCF₃ F 5-OCH₃ CN H A-621. OCF₃ CH₃ 3-F CN H A-622. OCF₃ CH₃ 3-CH₃ CN H A-623. OCF₃ CH₃ 3-OCH₃ CN H A-624. OCF₃ CH₃ 5-F CN H A-625. OCF₃ CH₃ 5-CH₃ CN H A-626. OCF₃ CH₃ 5-OCH₃ CN H A-627. OCF₃ OCH₃ 3-F CN H A-628. OCF₃ OCH₃ 3-CH₃ CN H A-629. OCF₃ OCH₃ 3-OCH₃ CN H A-630. OCF₃ OCH₃ 5-F CN H A-631. OCF₃ OCH₃ 5-CH₃ CN H A-632. OCF₃ OCH₃ 5-OCH₃ CN H A-633. OCF₃ CN 3-F CN H A-634. OCF₃ CN 3-CH₃ CN H A-635. OCF₃ CN 3-OCH₃ CN H A-636. OCF₃ CN 5-F CN H A-637. OCF₃ CN 5-CH₃ CN H A-638. OCF₃ CN 5-OCH₃ CN H A-639. OCF₃ CH₂F 3-F CN H A-640. OCF₃ CH₂F 3-CH₃ CN H A-641. OCF₃ CH₂F 3-OCH₃ CN H A-642. OCF₃ CH₂F 5-F CN H A-643. OCF₃ CH₂F 5-CH₃ CN H A-644. OCF₃ CH₂F 5-OCH₃ CN H A-645. OCF₃ CHF₂ 3-F CN H A-646. OCF₃ CHF₂ 3-CH₃ CN H A-647. OCF₃ CHF₂ 3-OCH₃ CN H A-648. OCF₃ CHF₂ 5-F CN H A-649. OCF₃ CHF₂ 5-CH₃ CN H A-650. OCF₃ CHF₂ 5-OCH₃ CN H A-651. OCF₃ CF₃ 3-F CN H A-652. OCF₃ CF₃ 3-CH₃ CN H A-653. OCF₃ CF₃ 3-OCH₃ CN H A-654. OCF₃ CF₃ 5-F CN H A-655. OCF₃ CF₃ 5-CH₃ CN H A-656. OCF₃ CF₃ 5-OCH₃ CN H A-657. OCF₃ OCH₂F 3-F CN H A-658. OCF₃ OCH₂F 3-CH₃ CN H A-659. OCF₃ OCH₂F 3-OCH₃ CN H A-660. OCF₃ OCH₂F 5-F CN H A-661. OCF₃ OCH₂F 5-CH₃ CN H A-662. OCF₃ OCH₂F 5-OCH₃ CN H A-663. OCF₃ OCHF₂ 3-F CN H A-664. OCF₃ OCHF₂ 3-CH₃ CN H A-665. OCF₃ OCHF₂ 3-OCH₃ CN H A-666. OCF₃ OCHF₂ 5-F CN H A-667. OCF₃ OCHF₂ 5-CH₃ CN H A-668. OCF₃ OCHF₂ 5-OCH₃ CN H A-669. OCF₃ OCF₃ 3-F CN H A-670. OCF₃ OCF₃ 3-CH₃ CN H A-671. OCF₃ OCF₃ 3-OCH₃ CN H A-672. OCF₃ OCF₃ 5-F CN H A-673. OCF₃ OCF₃ 5-CH₃ CN H A-674. OCF₃ OCF₃ 5-OCH₃ CN H A-675. H H H F H A-676. F H H F H A-677. CH₃ H H F H A-678. OCH₃ H H F H A-679. CH₂F H H F H A-680. CHF₂ H H F H A-681. CF₃ H H F H A-682. OCH₂F H H F H A-683. OCHF₂ H H F H A-684. OCF₃ H H F H A-685. H F H F H A-686. H CH₃ H F H A-687. H OCH₃ H F H A-688. H CN H F H A-689. H CH₂F H F H A-690. H CHF₂ H F H A-691. H CF₃ H F H A-692. H OCH₂F H F H A-693. H OCHF₂ H F H A-694. H OCF₃ H F H A-695. H H 3-F F H A-696. H H 3-CH₃ F H A-697. H H 3-OCH₃ F H A-698. H H 5-F F H A-699. H H 5-CH₃ F H A-700. H H 5-OCH₃ F H A-701. F F H F H A-702. F CH₃ H F H A-703. F OCH₃ H F H A-704. F CN H F H A-705. F CH₂F H F H A-706. F CHF₂ H F H A-707. F CF₃ H F H A-708. F OCH₂F H F H A-709. F OCHF₂ H F H A-710. F OCF₃ H F H A-711. F H 3-F F H A-712. F H 3-CH₃ F H A-713. F H 3-OCH₃ F H A-714. F H 5-F F H A-715. F H 5-CH₃ F H A-716. F H 5-OCH₃ F H A-717. CH₃ F H F H A-718. CH₃ CH₃ H F H A-719. CH₃ OCH₃ H F H A-720. CH₃ CN H F H A-721. CH₃ CH₂F H F H A-722. CH₃ CHF₂ H F H A-723. CH₃ CF₃ H F H A-724. CH₃ OCH₂F H F H A-725. CH₃ OCHF₂ H F H A-726. CH₃ OCF₃ H F H A-727. CH₃ H 3-F F H A-728. CH₃ H 3-CH₃ F H A-729. CH₃ H 3-OCH₃ F H A-730. CH₃ H 5-F F H A-731. CH₃ H 5-CH₃ F H A-732. CH₃ H 5-OCH₃ F H A-733. OCH₃ F H F H A-734. OCH₃ CH₃ H F H A-735. OCH₃ OCH₃ H F H A-736. OCH₃ CN H F H A-737. OCH₃ CH₂F H F H A-738. OCH₃ CHF₂ H F H A-739. OCH₃ CF₃ H F H A-740. OCH₃ OCH₂F H F H A-741. OCH₃ OCHF₂ H F H A-742. OCH₃ OCF₃ H F H A-743. OCH₃ H 3-F F H A-744. OCH₃ H 3-CH₃ F H A-745. OCH₃ H 3-OCH₃ F H A-746. OCH₃ H 5-F F H A-747. OCH₃ H 5-CH₃ F H A-748. OCH₃ H 5-OCH₃ F H A-749. H F 3-F F H A-750. H F 3-CH₃ F H A-751. H F 3-OCH₃ F H A-752. H F 5-F F H A-753. H F 5-CH₃ F H A-754. H F 5-OCH₃ F H A-755. H CH₃ 3-F F H A-756. H CH₃ 3-CH₃ F H A-757. H CH₃ 3-OCH₃ F H A-758. H CH₃ 5-F F H A-759. H CH₃ 5-CH₃ F H A-760. H CH₃ 5-OCH₃ F H A-761. H OCH₃ 3-F F H A-762. H OCH₃ 3-CH₃ F H A-763. H OCH₃ 3-OCH₃ F H A-764. H OCH₃ 5-F F H A-765. H OCH₃ 5-CH₃ F H A-766. H OCH₃ 5-OCH₃ F H A-767. H CN 3-F F H A-768. H CN 3-CH₃ F H A-769. H CN 3-OCH₃ F H A-770. H CN 5-F F H A-771. H CN 5-CH₃ F H A-772. H CN 5-OCH₃ F H A-773. H CH₂F 3-F F H A-774. H CH₂F 3-CH₃ F H A-775. H CH₂F 3-OCH₃ F H A-776. H CH₂F 5-F F H A-777. H CH₂F 5-CH₃ F H A-778. H CH₂F 5-OCH₃ F H A-779. H CHF₂ 3-F F H A-780. H CHF₂ 3-CH₃ F H A-781. H CHF₂ 3-OCH₃ F H A-782. H CHF₂ 5-F F H A-783. H CHF₂ 5-CH₃ F H A-784. H CHF₂ 5-OCH₃ F H A-785. H CF₃ 3-F F H A-786. H CF₃ 3-CH₃ F H A-787. H CF₃ 3-OCH₃ F H A-788. H CF₃ 5-F F H A-789. H CF₃ 5-CH₃ F H A-790. H CF₃ 5-OCH₃ F H A-791. H OCH₂F 3-F F H A-792. H OCH₂F 3-CH₃ F H A-793. H OCH₂F 3-OCH₃ F H A-794. H OCH₂F 5-F F H A-795. H OCH₂F 5-CH₃ F H A-796. H OCH₂F 5-OCH₃ F H A-797. H OCHF₂ 3-F F H A-798. H OCHF₂ 3-CH₃ F H A-799. H OCHF₂ 3-OCH₃ F H A-800. H OCHF₂ 5-F F H A-801. H OCHF₂ 5-CH₃ F H A-802. H OCHF₂ 5-OCH₃ F H A-803. H OCF₃ 3-F F H A-804. H OCF₃ 3-CH₃ F H A-805. H OCF₃ 3-OCH₃ F H A-806. H OCF₃ 5-F F H A-807. H OCF₃ 5-CH₃ F H A-808. H OCF₃ 5-OCH₃ F H A-809. F F 3-F F H A-810. F F 3-CH₃ F H A-811. F F 3-OCH₃ F H A-812. F F 5-F F H A-813. F F 5-CH₃ F H A-814. F F 5-OCH₃ F H A-815. F CH₃ 3-F F H A-816. F CH₃ 3-CH₃ F H A-817. F CH₃ 3-OCH₃ F H A-818. F CH₃ 5-F F H A-819. F CH₃ 5-CH₃ F H A-820. F CH₃ 5-OCH₃ F H A-821. F OCH₃ 3-F F H A-822. F OCH₃ 3-CH₃ F H A-823. F OCH₃ 3-OCH₃ F H A-824. F OCH₃ 5-F F H A-825. F OCH₃ 5-CH₃ F H A-826. F OCH₃ 5-OCH₃ F H A-827. F CN 3-F F H A-828. F CN 3-CH₃ F H A-829. F CN 3-OCH₃ F H A-830. F CN 5-F F H A-831. F CN 5-CH₃ F H A-832. F CN 5-OCH₃ F H A-833. F CH₂F 3-F F H A-834. F CH₂F 3-CH₃ F H A-835. F CH₂F 3-OCH₃ F H A-836. F CH₂F 5-F F H A-837. F CH₂F 5-CH₃ F H A-838. F CH₂F 5-OCH₃ F H A-839. F CHF₂ 3-F F H A-840. F CHF₂ 3-CH₃ F H A-841. F CHF₂ 3-OCH₃ F H A-842. F CHF₂ 5-F F H A-843. F CHF₂ 5-CH₃ F H A-844. F CHF₂ 5-OCH₃ F H A-845. F CF₃ 3-F F H A-846. F CF₃ 3-CH₃ F H A-847. F CF₃ 3-OCH₃ F H A-848. F CF₃ 5-F F H A-849. F CF₃ 5-CH₃ F H A-850. F CF₃ 5-OCH₃ F H A-851. F OCH₂F 3-F F H A-852. F OCH₂F 3-CH₃ F H A-853. F OCH₂F 3-OCH₃ F H A-854. F OCH₂F 5-F F H A-855. F OCH₂F 5-CH₃ F H A-856. F OCH₂F 5-OCH₃ F H A-857. F OCHF₂ 3-F F H A-858. F OCHF₂ 3-CH₃ F H A-859. F OCHF₂ 3-OCH₃ F H A-860. F OCHF₂ 5-F F H A-861. F OCHF₂ 5-CH₃ F H A-862. F OCHF₂ 5-OCH₃ F H A-863. F OCF₃ 3-F F H A-864. F OCF₃ 3-CH₃ F H A-865. F OCF₃ 3-OCH₃ F H A-866. F OCF₃ 5-F F H A-867. F OCF₃ 5-CH₃ F H A-868. F OCF₃ 5-OCH₃ F H A-869. CH₃ F 3-F F H A-870. CH₃ F 3-CH₃ F H A-871. CH₃ F 3-OCH₃ F H A-872. CH₃ F 5-F F H A-873. CH₃ F 5-CH₃ F H A-874. CH₃ F 5-OCH₃ F H A-875. CH₃ CH₃ 3-F F H A-876. CH₃ CH₃ 3-CH₃ F H A-877. CH₃ CH₃ 3-OCH₃ F H A-878. CH₃ CH₃ 5-F F H A-879. CH₃ CH₃ 5-CH₃ F H A-880. CH₃ CH₃ 5-OCH₃ F H A-881. CH₃ OCH₃ 3-F F H A-882. CH₃ OCH₃ 3-CH₃ F H A-883. CH₃ OCH₃ 3-OCH₃ F H A-884. CH₃ OCH₃ 5-F F H A-885. CH₃ OCH₃ 5-CH₃ F H A-886. CH₃ OCH₃ 5-OCH₃ F H A-887. CH₃ CN 3-F F H A-888. CH₃ CN 3-CH₃ F H A-889. CH₃ CN 3-OCH₃ F H A-890. CH₃ CN 5-F F H A-891. CH₃ CN 5-CH₃ F H A-892. CH₃ CN 5-OCH₃ F H A-893. CH₃ CH₂F 3-F F H A-894. CH₃ CH₂F 3-CH₃ F H A-895. CH₃ CH₂F 3-OCH₃ F H A-896. CH₃ CH₂F 5-F F H A-897. CH₃ CH₂F 5-CH₃ F H A-898. CH₃ CH₂F 5-OCH₃ F H A-899. CH₃ CHF₂ 3-F F H A-900. CH₃ CHF₂ 3-CH₃ F H A-901. CH₃ CHF₂ 3-OCH₃ F H A-902. CH₃ CHF₂ 5-F F H A-903. CH₃ CHF₂ 5-CH₃ F H A-904. CH₃ CHF₂ 5-OCH₃ F H A-905. CH₃ CF₃ 3-F F H A-906. CH₃ CF₃ 3-CH₃ F H A-907. CH₃ CF₃ 3-OCH₃ F H A-908. CH₃ CF₃ 5-F F H A-909. CH₃ CF₃ 5-CH₃ F H A-910. CH₃ CF₃ 5-OCH₃ F H A-911. CH₃ OCH₂F 3-F F H A-912. CH₃ OCH₂F 3-CH₃ F H A-913. CH₃ OCH₂F 3-OCH₃ F H A-914. CH₃ OCH₂F 5-F F H A-915. CH₃ OCH₂F 5-CH₃ F H A-916. CH₃ OCH₂F 5-OCH₃ F H A-917. CH₃ OCHF₂ 3-F F H A-918. CH₃ OCHF₂ 3-CH₃ F H A-919. CH₃ OCHF₂ 3-OCH₃ F H A-920. CH₃ OCHF₂ 5-F F H A-921. CH₃ OCHF₂ 5-CH₃ F H A-922. CH₃ OCHF₂ 5-OCH₃ F H A-923. CH₃ OCF₃ 3-F F H A-924. CH₃ OCF₃ 3-CH₃ F H A-925. CH₃ OCF₃ 3-OCH₃ F H A-926. CH₃ OCF₃ 5-F F H A-927. CH₃ OCF₃ 5-CH₃ F H A-928. CH₃ OCF₃ 5-OCH₃ F H A-929. OCH₃ F 3-F F H A-930. OCH₃ F 3-CH₃ F H A-931. OCH₃ F 3-OCH₃ F H A-932. OCH₃ F 5-F F H A-933. OCH₃ F 5-CH₃ F H A-934. OCH₃ F 5-OCH₃ F H A-935. OCH₃ CH₃ 3-F F H A-936. OCH₃ CH₃ 3-CH₃ F H A-937. OCH₃ CH₃ 3-OCH₃ F H A-938. OCH₃ CH₃ 5-F F H A-939. OCH₃ CH₃ 5-CH₃ F H A-940. OCH₃ CH₃ 5-OCH₃ F H A-941. OCH₃ OCH₃ 3-F F H A-942. OCH₃ OCH₃ 3-CH₃ F H A-943. OCH₃ OCH₃ 3-OCH₃ F H A-944. OCH₃ OCH₃ 5-F F H A-945. OCH₃ OCH₃ 5-CH₃ F H A-946. OCH₃ OCH₃ 5-OCH₃ F H A-947. OCH₃ CN 3-F F H A-948. OCH₃ CN 3-CH₃ F H A-949. OCH₃ CN 3-OCH₃ F H A-950. OCH₃ CN 5-F F H A-951. OCH₃ CN 5-CH₃ F H A-952. OCH₃ CN 5-OCH₃ F H A-953. OCH₃ CH₂F 3-F F H A-954. OCH₃ CH₂F 3-CH₃ F H A-955. OCH₃ CH₂F 3-OCH₃ F H A-956. OCH₃ CH₂F 5-F F H A-957. OCH₃ CH₂F 5-CH₃ F H A-958. OCH₃ CH₂F 5-OCH₃ F H A-959. OCH₃ CHF₂ 3-F F H A-960. OCH₃ CHF₂ 3-CH₃ F H A-961. OCH₃ CHF₂ 3-OCH₃ F H A-962. OCH₃ CHF₂ 5-F F H A-963. OCH₃ CHF₂ 5-CH₃ F H A-964. OCH₃ CHF₂ 5-OCH₃ F H A-965. OCH₃ CF₃ 3-F F H A-966. OCH₃ CF₃ 3-CH₃ F H A-967. OCH₃ CF₃ 3-OCH₃ F H A-968. OCH₃ CF₃ 5-F F H A-969. OCH₃ CF₃ 5-CH₃ F H A-970. OCH₃ CF₃ 5-OCH₃ F H A-971. OCH₃ OCH₂F 3-F F H A-972. OCH₃ OCH₂F 3-CH₃ F H A-973. OCH₃ OCH₂F 3-OCH₃ F H A-974. OCH₃ OCH₂F 5-F F H A-975. OCH₃ OCH₂F 5-CH₃ F H A-976. OCH₃ OCH₂F 5-OCH₃ F H A-977. OCH₃ OCHF₂ 3-F F H A-978. OCH₃ OCHF₂ 3-CH₃ F H A-979. OCH₃ OCHF₂ 3-OCH₃ F H A-980. OCH₃ OCHF₂ 5-F F H A-981. OCH₃ OCHF₂ 5-CH₃ F H A-982. OCH₃ OCHF₂ 5-OCH₃ F H A-983. OCH₃ OCF₃ 3-F F H A-984. OCH₃ OCF₃ 3-CH₃ F H A-985. OCH₃ OCF₃ 3-OCH₃ F H A-986. OCH₃ OCF₃ 5-F F H A-987. OCH₃ OCF₃ 5-CH₃ F H A-988. OCH₃ OCF₃ 5-OCH₃ F H A-989. CH₂F F 3-F F H A-990. CH₂F F 3-CH₃ F H A-991. CH₂F F 3-OCH₃ F H A-992. CH₂F F 5-F F H A-993. CH₂F F 5-CH₃ F H A-994. CH₂F F 5-OCH₃ F H A-995. CH₂F CH₃ 3-F F H A-996. CH₂F CH₃ 3-CH₃ F H A-997. CH₂F CH₃ 3-OCH₃ F H A-998. CH₂F CH₃ 5-F F H A-999. CH₂F CH₃ 5-CH₃ F H A-1000. CH₂F CH₃ 5-OCH₃ F H A-1001. CH₂F OCH₃ 3-F F H A-1002. CH₂F OCH₃ 3-CH₃ F H A-1003. CH₂F OCH₃ 3-OCH₃ F H A-1004. CH₂F OCH₃ 5-F F H A-1005. CH₂F OCH₃ 5-CH₃ F H A-1006. CH₂F OCH₃ 5-OCH₃ F H A-1007. CH₂F CN 3-F F H A-1008. CH₂F CN 3-CH₃ F H A-1009. CH₂F CN 3-OCH₃ F H A-1010. CH₂F CN 5-F F H A-1011. CH₂F CN 5-CH₃ F H A-1012. CH₂F CN 5-OCH₃ F H A-1013. CH₂F CH₂F 3-F F H A-1014. CH₂F CH₂F 3-CH₃ F H A-1015. CH₂F CH₂F 3-OCH₃ F H A-1016. CH₂F CH₂F 5-F F H A-1017. CH₂F CH₂F 5-CH₃ F H A-1018. CH₂F CH₂F 5-OCH₃ F H A-1019. CH₂F CHF₂ 3-F F H A-1020. CH₂F CHF₂ 3-CH₃ F H A-1021. CH₂F CHF₂ 3-OCH₃ F H A-1022. CH₂F CHF₂ 5-F F H A-1023. CH₂F CHF₂ 5-CH₃ F H A-1024. CH₂F CHF₂ 5-OCH₃ F H A-1025. CH₂F CF₃ 3-F F H A-1026. CH₂F CF₃ 3-CH₃ F H A-1027. CH₂F CF₃ 3-OCH₃ F H A-1028. CH₂F CF₃ 5-F F H A-1029. CH₂F CF₃ 5-CH₃ F H A-1030. CH₂F CF₃ 5-OCH₃ F H A-1031. CH₂F OCH₂F 3-F F H A-1032. CH₂F OCH₂F 3-CH₃ F H A-1033. CH₂F OCH₂F 3-OCH₃ F H A-1034. CH₂F OCH₂F 5-F F H A-1035. CH₂F OCH₂F 5-CH₃ F H A-1036. CH₂F OCH₂F 5-OCH₃ F H A-1037. CH₂F OCHF₂ 3-F F H A-1038. CH₂F OCHF₂ 3-CH₃ F H A-1039. CH₂F OCHF₂ 3-OCH₃ F H A-1040. CH₂F OCHF₂ 5-F F H A-1041. CH₂F OCHF₂ 5-CH₃ F H A-1042. CH₂F OCHF₂ 5-OCH₃ F H A-1043. CH₂F OCF₃ 3-F F H A-1044. CH₂F OCF₃ 3-CH₃ F H A-1045. CH₂F OCF₃ 3-OCH₃ F H A-1046. CH₂F OCF₃ 5-F F H A-1047. CH₂F OCF₃ 5-CH₃ F H A-1048. CH₂F OCF₃ 5-OCH₃ F H A-1049. CHF₂ F 3-F F H A-1050. CHF₂ F 3-CH₃ F H A-1051. CHF₂ F 3-OCH₃ F H A-1052. CHF₂ F 5-F F H A-1053. CHF₂ F 5-CH₃ F H A-1054. CHF₂ F 5-OCH₃ F H A-1055. CHF₂ CH₃ 3-F F H A-1056. CHF₂ CH₃ 3-CH₃ F H A-1057. CHF₂ CH₃ 3-OCH₃ F H A-1058. CHF₂ CH₃ 5-F F H A-1059. CHF₂ CH₃ 5-CH₃ F H A-1060. CHF₂ CH₃ 5-OCH₃ F H A-1061. CHF₂ OCH₃ 3-F F H A-1062. CHF₂ OCH₃ 3-CH₃ F H A-1063. CHF₂ OCH₃ 3-OCH₃ F H A-1064. CHF₂ OCH₃ 5-F F H A-1065. CHF₂ OCH₃ 5-CH₃ F H A-1066. CHF₂ OCH₃ 5-OCH₃ F H A-1067. CHF₂ CN 3-F F H A-1068. CHF₂ CN 3-CH₃ F H A-1069. CHF₂ CN 3-OCH₃ F H A-1070. CHF₂ CN 5-F F H A-1071. CHF₂ CN 5-CH₃ F H A-1072. CHF₂ CN 5-OCH₃ F H A-1073. CHF₂ CH₂F 3-F F H A-1074. CHF₂ CH₂F 3-CH₃ F H A-1075. CHF₂ CH₂F 3-OCH₃ F H A-1076. CHF₂ CH₂F 5-F F H A-1077. CHF₂ CH₂F 5-CH₃ F H A-1078. CHF₂ CH₂F 5-OCH₃ F H A-1079. CHF₂ CHF₂ 3-F F H A-1080. CHF₂ CHF₂ 3-CH₃ F H A-1081. CHF₂ CHF₂ 3-OCH₃ F H A-1082. CHF₂ CHF₂ 5-F F H A-1083. CHF₂ CHF₂ 5-CH₃ F H A-1084. CHF₂ CHF₂ 5-OCH₃ F H A-1085. CHF₂ CF₃ 3-F F H A-1086. CHF₂ CF₃ 3-CH₃ F H A-1087. CHF₂ CF₃ 3-OCH₃ F H A-1088. CHF₂ CF₃ 5-F F H A-1089. CHF₂ CF₃ 5-CH₃ F H A-1090. CHF₂ CF₃ 5-OCH₃ F H A-1091. CHF₂ OCH₂F 3-F F H A-1092. CHF₂ OCH₂F 3-CH₃ F H A-1093. CHF₂ OCH₂F 3-OCH₃ F H A-1094. CHF₂ OCH₂F 5-F F H A-1095. CHF₂ OCH₂F 5-CH₃ F H A-1096. CHF₂ OCH₂F 5-OCH₃ F H A-1097. CHF₂ OCHF₂ 3-F F H A-1098. CHF₂ OCHF₂ 3-CH₃ F H A-1099. CHF₂ OCHF₂ 3-OCH₃ F H A-1100. CHF₂ OCHF₂ 5-F F H A-1101. CHF₂ OCHF₂ 5-CH₃ F H A-1102. CHF₂ OCHF₂ 5-OCH₃ F H A-1103. CHF₂ OCF₃ 3-F F H A-1104. CHF₂ OCF₃ 3-CH₃ F H A-1105. CHF₂ OCF₃ 3-OCH₃ F H A-1106. CHF₂ OCF₃ 5-F F H A-1107. CHF₂ OCF₃ 5-CH₃ F H A-1108. CHF₂ OCF₃ 5-OCH₃ F H A-1109. CF₃ F 3-F F H A-1110. CF₃ F 3-CH₃ F H A-1111. CF₃ F 3-OCH₃ F H A-1112. CF₃ F 5-F F H A-1113. CF₃ F 5-CH₃ F H A-1114. CF₃ F 5-OCH₃ F H A-1115. CF₃ CH₃ 3-F F H A-1116. CF₃ CH₃ 3-CH₃ F H A-1117. CF₃ CH₃ 3-OCH₃ F H A-1118. CF₃ CH₃ 5-F F H A-1119. CF₃ CH₃ 5-CH₃ F H A-1120. CF₃ CH₃ 5-OCH₃ F H A-1121. CF₃ OCH₃ 3-F F H A-1122. CF₃ OCH₃ 3-CH₃ F H A-1123. CF₃ OCH₃ 3-OCH₃ F H A-1124. CF₃ OCH₃ 5-F F H A-1125. CF₃ OCH₃ 5-CH₃ F H A-1126. CF₃ OCH₃ 5-OCH₃ F H A-1127. CF₃ CN 3-F F H A-1128. CF₃ CN 3-CH₃ F H A-1129. CF₃ CN 3-OCH₃ F H A-1130. CF₃ CN 5-F F H A-1131. CF₃ CN 5-CH₃ F H A-1132. CF₃ CN 5-OCH₃ F H A-1133. CF₃ CH₂F 3-F F H A-1134. CF₃ CH₂F 3-CH₃ F H A-1135. CF₃ CH₂F 3-OCH₃ F H A-1136. CF₃ CH₂F 5-F F H A-1137. CF₃ CH₂F 5-CH₃ F H A-1138. CF₃ CH₂F 5-OCH₃ F H A-1139. CF₃ CHF₂ 3-F F H A-1140. CF₃ CHF₂ 3-CH₃ F H A-1141. CF₃ CHF₂ 3-OCH₃ F H A-1142. CF₃ CHF₂ 5-F F H A-1143. CF₃ CHF₂ 5-CH₃ F H A-1144. CF₃ CHF₂ 5-OCH₃ F H A-1145. CF₃ CF₃ 3-F F H A-1146. CF₃ CF₃ 3-CH₃ F H A-1147. CF₃ CF₃ 3-OCH₃ F H A-1148. CF₃ CF₃ 5-F F H A-1149. CF₃ CF₃ 5-CH₃ F H A-1150. CF₃ CF₃ 5-OCH₃ F H A-1151. CF₃ OCH₂F 3-F F H A-1152. CF₃ OCH₂F 3-CH₃ F H A-1153. CF₃ OCH₂F 3-OCH₃ F H A-1154. CF₃ OCH₂F 5-F F H A-1155. CF₃ OCH₂F 5-CH₃ F H A-1156. CF₃ OCH₂F 5-OCH₃ F H A-1157. CF₃ OCHF₂ 3-F F H A-1158. CF₃ OCHF₂ 3-CH₃ F H A-1159. CF₃ OCHF₂ 3-OCH₃ F H A-1160. CF₃ OCHF₂ 5-F F H A-1161. CF₃ OCHF₂ 5-CH₃ F H A-1162. CF₃ OCHF₂ 5-OCH₃ F H A-1163. CF₃ OCF₃ 3-F F H A-1164. CF₃ OCF₃ 3-CH₃ F H A-1165. CF₃ OCF₃ 3-OCH₃ F H A-1166. CF₃ OCF₃ 5-F F H A-1167. CF₃ OCF₃ 5-CH₃ F H A-1168. CF₃ OCF₃ 5-OCH₃ F H A-1169. OCH₂F F 3-F F H A-1170. OCH₂F F 3-CH₃ F H A-1171. OCH₂F F 3-OCH₃ F H A-1172. OCH₂F F 5-F F H A-1173. OCH₂F F 5-CH₃ F H A-1174. OCH₂F F 5-OCH₃ F H A-1175. OCH₂F CH₃ 3-F F H A-1176. OCH₂F CH₃ 3-CH₃ F H A-1177. OCH₂F CH₃ 3-OCH₃ F H A-1178. OCH₂F CH₃ 5-F F H A-1179. OCH₂F CH₃ 5-CH₃ F H A-1180. OCH₂F CH₃ 5-OCH₃ F H A-1181. OCH₂F OCH₃ 3-F F H A-1182. OCH₂F OCH₃ 3-CH₃ F H A-1183. OCH₂F OCH₃ 3-OCH₃ F H A-1184. OCH₂F OCH₃ 5-F F H A-1185. OCH₂F OCH₃ 5-CH₃ F H A-1186. OCH₂F OCH₃ 5-OCH₃ F H A-1187. OCH₂F CN 3-F F H A-1188. OCH₂F CN 3-CH₃ F H A-1189. OCH₂F CN 3-OCH₃ F H A-1190. OCH₂F CN 5-F F H A-1191. OCH₂F CN 5-CH₃ F H A-1192. OCH₂F CN 5-OCH₃ F H A-1193. OCH₂F CH₂F 3-F F H A-1194. OCH₂F CH₂F 3-CH₃ F H A-1195. OCH₂F CH₂F 3-OCH₃ F H A-1196. OCH₂F CH₂F 5-F F H A-1197. OCH₂F CH₂F 5-CH₃ F H A-1198. OCH₂F CH₂F 5-OCH₃ F H A-1199. OCH₂F CHF₂ 3-F F H A-1200. OCH₂F CHF₂ 3-CH₃ F H A-1201. OCH₂F CHF₂ 3-OCH₃ F H A-1202. OCH₂F CHF₂ 5-F F H A-1203. OCH₂F CHF₂ 5-CH₃ F H A-1204. OCH₂F CHF₂ 5-OCH₃ F H A-1205. OCH₂F CF₃ 3-F F H A-1206. OCH₂F CF₃ 3-CH₃ F H A-1207. OCH₂F CF₃ 3-OCH₃ F H A-1208. OCH₂F CF₃ 5-F F H A-1209. OCH₂F CF₃ 5-CH₃ F H A-1210. OCH₂F CF₃ 5-OCH₃ F H A-1211. OCH₂F OCH₂F 3-F F H A-1212. OCH₂F OCH₂F 3-CH₃ F H A-1213. OCH₂F OCH₂F 3-OCH₃ F H A-1214. OCH₂F OCH₂F 5-F F H A-1215. OCH₂F OCH₂F 5-CH₃ F H A-1216. OCH₂F OCH₂F 5-OCH₃ F H A-1217. OCH₂F OCHF₂ 3-F F H A-1218. OCH₂F OCHF₂ 3-CH₃ F H A-1219. OCH₂F OCHF₂ 3-OCH₃ F H A-1220. OCH₂F OCHF₂ 5-F F H A-1221. OCH₂F OCHF₂ 5-CH₃ F H A-1222. OCH₂F OCHF₂ 5-OCH₃ F H A-1223. OCH₂F OCF₃ 3-F F H A-1224. OCH₂F OCF₃ 3-CH₃ F H A-1225. OCH₂F OCF₃ 3-OCH₃ F H A-1226. OCH₂F OCF₃ 5-F F H A-1227. OCH₂F OCF₃ 5-CH₃ F H A-1228. OCH₂F OCF₃ 5-OCH₃ F H A-1229. OCHF₂ F 3-F F H A-1230. OCHF₂ F 3-CH₃ F H A-1231. OCHF₂ F 3-OCH₃ F H A-1232. OCHF₂ F 5-F F H A-1233. OCHF₂ F 5-CH₃ F H A-1234. OCHF₂ F 5-OCH₃ F H A-1235. OCHF₂ CH₃ 3-F F H A-1236. OCHF₂ CH₃ 3-CH₃ F H A-1237. OCHF₂ CH₃ 3-OCH₃ F H A-1238. OCHF₂ CH₃ 5-F F H A-1239. OCHF₂ CH₃ 5-CH₃ F H A-1240. OCHF₂ CH₃ 5-OCH₃ F H A-1241. OCHF₂ OCH₃ 3-F F H A-1242. OCHF₂ OCH₃ 3-CH₃ F H A-1243. OCHF₂ OCH₃ 3-OCH₃ F H A-1244. OCHF₂ OCH₃ 5-F F H A-1245. OCHF₂ OCH₃ 5-CH₃ F H A-1246. OCHF₂ OCH₃ 5-OCH₃ F H A-1247. OCHF₂ CN 3-F F H A-1248. OCHF₂ CN 3-CH₃ F H A-1249. OCHF₂ CN 3-OCH₃ F H A-1250. OCHF₂ CN 5-F F H A-1251. OCHF₂ CN 5-CH₃ F H A-1252. OCHF₂ CN 5-OCH₃ F H A-1253. OCHF₂ CH₂F 3-F F H A-1254. OCHF₂ CH₂F 3-CH₃ F H A-1255. OCHF₂ CH₂F 3-OCH₃ F H A-1256. OCHF₂ CH₂F 5-F F H A-1257. OCHF₂ CH₂F 5-CH₃ F H A-1258. OCHF₂ CH₂F 5-OCH₃ F H A-1259. OCHF₂ CHF₂ 3-F F H A-1260. OCHF₂ CHF₂ 3-CH₃ F H A-1261. OCHF₂ CHF₂ 3-OCH₃ F H A-1262. OCHF₂ CHF₂ 5-F F H A-1263. OCHF₂ CHF₂ 5-CH₃ F H A-1264. OCHF₂ CHF₂ 5-OCH₃ F H A-1265. OCHF₂ CF₃ 3-F F H A-1266. OCHF₂ CF₃ 3-CH₃ F H A-1267. OCHF₂ CF₃ 3-OCH₃ F H A-1268. OCHF₂ CF₃ 5-F F H A-1269. OCHF₂ CF₃ 5-CH₃ F H A-1270. OCHF₂ CF₃ 5-OCH₃ F H A-1271. OCHF₂ OCH₂F 3-F F H A-1272. OCHF₂ OCH₂F 3-CH₃ F H A-1273. OCHF₂ OCH₂F 3-OCH₃ F H A-1274. OCHF₂ OCH₂F 5-F F H A-1275. OCHF₂ OCH₂F 5-CH₃ F H A-1276. OCHF₂ OCH₂F 5-OCH₃ F H A-1277. OCHF₂ OCHF₂ 3-F F H A-1278. OCHF₂ OCHF₂ 3-CH₃ F H A-1279. OCHF₂ OCHF₂ 3-OCH₃ F H A-1280. OCHF₂ OCHF₂ 5-F F H A-1281. OCHF₂ OCHF₂ 5-CH₃ F H A-1282. OCHF₂ OCHF₂ 5-OCH₃ F H A-1283. OCHF₂ OCF₃ 3-F F H A-1284. OCHF₂ OCF₃ 3-CH₃ F H A-1285. OCHF₂ OCF₃ 3-OCH₃ F H A-1286. OCHF₂ OCF₃ 5-F F H A-1287. OCHF₂ OCF₃ 5-CH₃ F H A-1288. OCHF₂ OCF₃ 5-OCH₃ F H A-1289. OCF₃ F 3-F F H A-1290. OCF₃ F 3-CH₃ F H A-1291. OCF₃ F 3-OCH₃ F H A-1292. OCF₃ F 5-F F H A-1293. OCF₃ F 5-CH₃ F H A-1294. OCF₃ F 5-OCH₃ F H A-1295. OCF₃ CH₃ 3-F F H A-1296. OCF₃ CH₃ 3-CH₃ F H A-1297. OCF₃ CH₃ 3-OCH₃ F H A-1298. OCF₃ CH₃ 5-F F H A-1299. OCF₃ CH₃ 5-CH₃ F H A-1300. OCF₃ CH₃ 5-OCH₃ F H A-1301. OCF₃ OCH₃ 3-F F H A-1302. OCF₃ OCH₃ 3-CH₃ F H A-1303. OCF₃ OCH₃ 3-OCH₃ F H A-1304. OCF₃ OCH₃ 5-F F H A-1305. OCF₃ OCH₃ 5-CH₃ F H A-1306. OCF₃ OCH₃ 5-OCH₃ F H A-1307. OCF₃ CN 3-F F H A-1308. OCF₃ CN 3-CH₃ F H A-1309. OCF₃ CN 3-OCH₃ F H A-1310. OCF₃ CN 5-F F H A-1311. OCF₃ CN 5-CH₃ F H A-1312. OCF₃ CN 5-OCH₃ F H A-1313. OCF₃ CH₂F 3-F F H A-1314. OCF₃ CH₂F 3-CH₃ F H A-1315. OCF₃ CH₂F 3-OCH₃ F H A-1316. OCF₃ CH₂F 5-F F H A-1317. OCF₃ CH₂F 5-CH₃ F H A-1318. OCF₃ CH₂F 5-OCH₃ F H A-1319. OCF₃ CHF₂ 3-F F H A-1320. OCF₃ CHF₂ 3-CH₃ F H A-1321. OCF₃ CHF₂ 3-OCH₃ F H A-1322. OCF₃ CHF₂ 5-F F H A-1323. OCF₃ CHF₂ 5-CH₃ F H A-1324. OCF₃ CHF₂ 5-OCH₃ F H A-1325. OCF₃ CF₃ 3-F F H A-1326. OCF₃ CF₃ 3-CH₃ F H A-1327. OCF₃ CF₃ 3-OCH₃ F H A-1328. OCF₃ CF₃ 5-F F H A-1329. OCF₃ CF₃ 5-CH₃ F H A-1330. OCF₃ CF₃ 5-OCH₃ F H A-1331. OCF₃ OCH₂F 3-F F H A-1332. OCF₃ OCH₂F 3-CH₃ F H A-1333. OCF₃ OCH₂F 3-OCH₃ F H A-1334. OCF₃ OCH₂F 5-F F H A-1335. OCF₃ OCH₂F 5-CH₃ F H A-1336. OCF₃ OCH₂F 5-OCH₃ F H A-1337. OCF₃ OCHF₂ 3-F F H A-1338. OCF₃ OCHF₂ 3-CH₃ F H A-1339. OCF₃ OCHF₂ 3-OCH₃ F H A-1340. OCF₃ OCHF₂ 5-F F H A-1341. OCF₃ OCHF₂ 5-CH₃ F H A-1342. OCF₃ OCHF₂ 5-OCH₃ F H A-1343. OCF₃ OCF₃ 3-F F H A-1344. OCF₃ OCF₃ 3-CH₃ F H A-1345. OCF₃ OCF₃ 3-OCH₃ F H A-1346. OCF₃ OCF₃ 5-F F H A-1347. OCF₃ OCF₃ 5-CH₃ F H A-1348. OCF₃ OCF₃ 5-OCH₃ F H A-1349. H H H Cl H A-1350. F H H Cl H A-1351. CH₃ H H Cl H A-1352. OCH₃ H H Cl H A-1353. CH₂F H H Cl H A-1354. CHF₂ H H Cl H A-1355. CF₃ H H Cl H A-1356. OCH₂F H H Cl H A-1357. OCHF₂ H H Cl H A-1358. OCF₃ H H Cl H A-1359. H F H Cl H A-1360. H CH₃ H Cl H A-1361. H OCH₃ H Cl H A-1362. H CN H Cl H A-1363. H CH₂F H Cl H A-1364. H CHF₂ H Cl H A-1365. H CF₃ H Cl H A-1366. H OCH₂F H Cl H A-1367. H OCHF₂ H Cl H A-1368. H OCF₃ H Cl H A-1369. H H 3-F Cl H A-1370. H H 3-CH₃ Cl H A-1371. H H 3-OCH₃ Cl H A-1372. H H 5-F Cl H A-1373. H H 5-CH₃ Cl H A-1374. H H 5-OCH₃ Cl H A-1375. F F H Cl H A-1376. F CH₃ H Cl H A-1377. F OCH₃ H Cl H A-1378. F CN H Cl H A-1379. F CH₂F H Cl H A-1380. F CHF₂ H Cl H A-1381. F CF₃ H Cl H A-1382. F OCH₂F H Cl H A-1383. F OCHF₂ H Cl H A-1384. F OCF₃ H Cl H A-1385. F H 3-F Cl H A-1386. F H 3-CH₃ Cl H A-1387. F H 3-OCH₃ Cl H A-1388. F H 5-F Cl H A-1389. F H 5-CH₃ Cl H A-1390. F H 5-OCH₃ Cl H A-1391. CH₃ F H Cl H A-1392. CH₃ CH₃ H Cl H A-1393. CH₃ OCH₃ H Cl H A-1394. CH₃ CN H Cl H A-1395. CH₃ CH₂F H Cl H A-1396. CH₃ CHF₂ H Cl H A-1397. CH₃ CF₃ H Cl H A-1398. CH₃ OCH₂F H Cl H A-1399. CH₃ OCHF₂ H Cl H A-1400. CH₃ OCF₃ H Cl H A-1401. CH₃ H 3-F Cl H A-1402. CH₃ H 3-CH₃ Cl H A-1403. CH₃ H 3-OCH₃ Cl H A-1404. CH₃ H 5-F Cl H A-1405. CH₃ H 5-CH₃ Cl H A-1406. CH₃ H 5-OCH₃ Cl H A-1407. OCH₃ F H Cl H A-1408. OCH₃ CH₃ H Cl H A-1409. OCH₃ OCH₃ H Cl H A-1410. OCH₃ CN H Cl H A-1411. OCH₃ CH₂F H Cl H A-1412. OCH₃ CHF₂ H Cl H A-1413. OCH₃ CF₃ H Cl H A-1414. OCH₃ OCH₂F H Cl H A-1415. OCH₃ OCHF₂ H Cl H A-1416. OCH₃ OCF₃ H Cl H A-1417. OCH₃ H 3-F Cl H A-1418. OCH₃ H 3-CH₃ Cl H A-1419. OCH₃ H 3-OCH₃ Cl H A-1420. OCH₃ H 5-F Cl H A-1421. OCH₃ H 5-CH₃ Cl H A-1422. OCH₃ H 5-OCH₃ Cl H A-1423. H F 3-F Cl H A-1424. H F 3-CH₃ Cl H A-1425. H F 3-OCH₃ Cl H A-1426. H F 5-F Cl H A-1427. H F 5-CH₃ Cl H A-1428. H F 5-OCH₃ Cl H A-1429. H CH₃ 3-F Cl H A-1430. H CH₃ 3-CH₃ Cl H A-1431. H CH₃ 3-OCH₃ Cl H A-1432. H CH₃ 5-F Cl H A-1433. H CH₃ 5-CH₃ Cl H A-1434. H CH₃ 5-OCH₃ Cl H A-1435. H OCH₃ 3-F Cl H A-1436. H OCH₃ 3-CH₃ Cl H A-1437. H OCH₃ 3-OCH₃ Cl H A-1438. H OCH₃ 5-F Cl H A-1439. H OCH₃ 5-CH₃ Cl H A-1440. H OCH₃ 5-OCH₃ Cl H A-1441. H CN 3-F Cl H A-1442. H CN 3-CH₃ Cl H A-1443. H CN 3-OCH₃ Cl H A-1444. H CN 5-F Cl H A-1445. H CN 5-CH₃ Cl H A-1446. H CN 5-OCH₃ Cl H A-1447. H CH₂F 3-F Cl H A-1448. H CH₂F 3-CH₃ Cl H A-1449. H CH₂F 3-OCH₃ Cl H A-1450. H CH₂F 5-F Cl H A-1451. H CH₂F 5-CH₃ Cl H A-1452. H CH₂F 5-OCH₃ Cl H A-1453. H CHF₂ 3-F Cl H A-1454. H CHF₂ 3-CH₃ Cl H A-1455. H CHF₂ 3-OCH₃ Cl H A-1456. H CHF₂ 5-F Cl H A-1457. H CHF₂ 5-CH₃ Cl H A-1458. H CHF₂ 5-OCH₃ Cl H A-1459. H CF₃ 3-F Cl H A-1460. H CF₃ 3-CH₃ Cl H A-1461. H CF₃ 3-OCH₃ Cl H A-1462. H CF₃ 5-F Cl H A-1463. H CF₃ 5-CH₃ Cl H A-1464. H CF₃ 5-OCH₃ Cl H A-1465. H OCH₂F 3-F Cl H A-1466. H OCH₂F 3-CH₃ Cl H A-1467. H OCH₂F 3-OCH₃ Cl H A-1468. H OCH₂F 5-F Cl H A-1469. H OCH₂F 5-CH₃ Cl H A-1470. H OCH₂F 5-OCH₃ Cl H A-1471. H OCHF₂ 3-F Cl H A-1472. H OCHF₂ 3-CH₃ Cl H A-1473. H OCHF₂ 3-OCH₃ Cl H A-1474. H OCHF₂ 5-F Cl H A-1475. H OCHF₂ 5-CH₃ Cl H A-1476. H OCHF₂ 5-OCH₃ Cl H A-1477. H OCF₃ 3-F Cl H A-1478. H OCF₃ 3-CH₃ Cl H A-1479. H OCF₃ 3-OCH₃ Cl H A-1480. H OCF₃ 5-F Cl H A-1481. H OCF₃ 5-CH₃ Cl H A-1482. H OCF₃ 5-OCH₃ Cl H A-1483. F F 3-F Cl H A-1484. F F 3-CH₃ Cl H A-1485. F F 3-OCH₃ Cl H A-1486. F F 5-F Cl H A-1487. F F 5-CH₃ Cl H A-1488. F F 5-OCH₃ Cl H A-1489. F CH₃ 3-F Cl H A-1490. F CH₃ 3-CH₃ Cl H A-1491. F CH₃ 3-OCH₃ Cl H A-1492. F CH₃ 5-F Cl H A-1493. F CH₃ 5-CH₃ Cl H A-1494. F CH₃ 5-OCH₃ Cl H A-1495. F OCH₃ 3-F Cl H A-1496. F OCH₃ 3-CH₃ Cl H A-1497. F OCH₃ 3-OCH₃ Cl H A-1498. F OCH₃ 5-F Cl H A-1499. F OCH₃ 5-CH₃ Cl H A-1500. F OCH₃ 5-OCH₃ Cl H A-1501. F CN 3-F Cl H A-1502. F CN 3-CH₃ Cl H A-1503. F CN 3-OCH₃ Cl H A-1504. F CN 5-F Cl H A-1505. F CN 5-CH₃ Cl H A-1506. F CN 5-OCH₃ Cl H A-1507. F CH₂F 3-F Cl H A-1508. F CH₂F 3-CH₃ Cl H A-1509. F CH₂F 3-OCH₃ Cl H A-1510. F CH₂F 5-F Cl H A-1511. F CH₂F 5-CH₃ Cl H A-1512. F CH₂F 5-OCH₃ Cl H A-1513. F CHF₂ 3-F Cl H A-1514. F CHF₂ 3-CH₃ Cl H A-1515. F CHF₂ 3-OCH₃ Cl H A-1516. F CHF₂ 5-F Cl H A-1517. F CHF₂ 5-CH₃ Cl H A-1518. F CHF₂ 5-OCH₃ Cl H A-2807. H CF₃ 3-F F F A-2808. H CF₃ 3-CH₃ F F A-2809. H CF₃ 3-OCH₃ F F A-2810. H CF₃ 5-F F F A-2811. H CF₃ 5-CH₃ F F A-2812. H CF₃ 5-OCH₃ F F A-2813. H OCH₂F 3-F F F A-2814. H OCH₂F 3-CH₃ F F A-2815. H OCH₂F 3-OCH₃ F F A-2816. H OCH₂F 5-F F F A-2817. H OCH₂F 5-CH₃ F F A-2818. H OCH₂F 5-OCH₃ F F A-2819. H OCHF₂ 3-F F F A-2820. H OCHF₂ 3-CH₃ F F A-2821. H OCHF₂ 3-OCH₃ F F A-2822. H OCHF₂ 5-F F F A-2823. H OCHF₂ 5-CH₃ F F A-2824. H OCHF₂ 5-OCH₃ F F A-2825. H OCF₃ 3-F F F A-2826. H OCF₃ 3-CH₃ F F A-2827. H OCF₃ 3-OCH₃ F F A-2828. H OCF₃ 5-F F F A-2829. H OCF₃ 5-CH₃ F F A-2830. H OCF₃ 5-OCH₃ F F A-2831. F F 3-F F F A-2832. F F 3-CH₃ F F A-2833. F F 3-OCH₃ F F A-2834. F F 5-F F F A-2835. F F 5-CH₃ F F A-2836. F F 5-OCH₃ F F A-2837. F CH₃ 3-F F F A-2838. F CH₃ 3-CH₃ F F A-2839. F CH₃ 3-OCH₃ F F A-2840. F CH₃ 5-F F F A-2841. F CH₃ 5-CH₃ F F A-2842. F CH₃ 5-OCH₃ F F A-2843. F OCH₃ 3-F F F A-2844. F OCH₃ 3-CH₃ F F A-2845. F OCH₃ 3-OCH₃ F F A-2846. F OCH₃ 5-F F F A-2847. F OCH₃ 5-CH₃ F F A-2848. F OCH₃ 5-OCH₃ F F A-2849. F CN 3-F F F A-2850. F CN 3-CH₃ F F A-2851. F CN 3-OCH₃ F F A-2852. F CN 5-F F F A-2853. F CN 5-CH₃ F F A-2854. F CN 5-OCH₃ F F A-2855. F CH₂F 3-F F F A-2856. F CH₂F 3-CH₃ F F A-2857. F CH₂F 3-OCH₃ F F A-2858. F CH₂F 5-F F F A-2859. F CH₂F 5-CH₃ F F A-2860. F CH₂F 5-OCH₃ F F A-2861. F CHF₂ 3-F F F A-2862. F CHF₂ 3-CH₃ F F A-2863. F CHF₂ 3-OCH₃ F F A-2864. F CHF₂ 5-F F F A-2865. F CHF₂ 5-CH₃ F F A-2866. F CHF₂ 5-OCH₃ F F A-2867. F CF₃ 3-F F F A-2868. F CF₃ 3-CH₃ F F A-2869. F CF₃ 3-OCH₃ F F A-2870. F CF₃ 5-F F F A-2871. F CF₃ 5-CH₃ F F A-2872. F CF₃ 5-OCH₃ F F A-2873. F OCH₂F 3-F F F A-2874. F OCH₂F 3-CH₃ F F A-2875. F OCH₂F 3-OCH₃ F F A-2876. F OCH₂F 5-F F F A-2877. F OCH₂F 5-CH₃ F F A-2878. F OCH₂F 5-OCH₃ F F A-2879. F OCHF₂ 3-F F F A-2880. F OCHF₂ 3-CH₃ F F A-2881. F OCHF₂ 3-OCH₃ F F A-2882. F OCHF₂ 5-F F F A-2883. F OCHF₂ 5-CH₃ F F A-2884. F OCHF₂ 5-OCH₃ F F A-2885. F OCF₃ 3-F F F A-2886. F OCF₃ 3-CH₃ F F A-2887. F OCF₃ 3-OCH₃ F F A-2888. F OCF₃ 5-F F F A-2889. F OCF₃ 5-CH₃ F F A-2890. F OCF₃ 5-OCH₃ F F A-2891. CH₃ F 3-F F F A-2892. CH₃ F 3-CH₃ F F A-2893. CH₃ F 3-OCH₃ F F A-2894. CH₃ F 5-F F F A-2895. CH₃ F 5-CH₃ F F A-2896. CH₃ F 5-OCH₃ F F A-2897. CH₃ CH₃ 3-F F F A-2898. CH₃ CH₃ 3-CH₃ F F A-2899. CH₃ CH₃ 3-OCH₃ F F A-2900. CH₃ CH₃ 5-F F F A-2901. CH₃ CH₃ 5-CH₃ F F A-2902. CH₃ CH₃ 5-OCH₃ F F A-2903. CH₃ OCH₃ 3-F F F A-2904. CH₃ OCH₃ 3-CH₃ F F A-2905. CH₃ OCH₃ 3-OCH₃ F F A-2906. CH₃ OCH₃ 5-F F F A-2907. CH₃ OCH₃ 5-CH₃ F F A-2908. CH₃ OCH₃ 5-OCH₃ F F A-2909. CH₃ CN 3-F F F A-2910. CH₃ CN 3-CH₃ F F A-2911. CH₃ CN 3-OCH₃ F F A-2912. CH₃ CN 5-F F F A-2913. CH₃ CN 5-CH₃ F F A-2914. CH₃ CN 5-OCH₃ F F A-2915. CH₃ CH₂F 3-F F F A-2916. CH₃ CH₂F 3-CH₃ F F A-2917. CH₃ CH₂F 3-OCH₃ F F A-2918. CH₃ CH₂F 5-F F F A-2919. CH₃ CH₂F 5-CH₃ F F A-2920. CH₃ CH₂F 5-OCH₃ F F A-2921. CH₃ CHF₂ 3-F F F A-2922. CH₃ CHF₂ 3-CH₃ F F A-2923. CH₃ CHF₂ 3-OCH₃ F F A-2924. CH₃ CHF₂ 5-F F F A-2925. CH₃ CHF₂ 5-CH₃ F F A-2926. CH₃ CHF₂ 5-OCH₃ F F A-2927. CH₃ CF₃ 3-F F F A-2928. CH₃ CF₃ 3-CH₃ F F A-2929. CH₃ CF₃ 3-OCH₃ F F A-2930. CH₃ CF₃ 5-F F F A-2931. CH₃ CF₃ 5-CH₃ F F A-2932. CH₃ CF₃ 5-OCH₃ F F A-2933. CH₃ OCH₂F 3-F F F A-2934. CH₃ OCH₂F 3-CH₃ F F A-2935. CH₃ OCH₂F 3-OCH₃ F F A-2936. CH₃ OCH₂F 5-F F F A-2937. CH₃ OCH₂F 5-CH₃ F F A-2938. CH₃ OCH₂F 5-OCH₃ F F A-2939. CH₃ OCHF₂ 3-F F F A-2940. CH₃ OCHF₂ 3-CH₃ F F A-2941. CH₃ OCHF₂ 3-OCH₃ F F A-2942. CH₃ OCHF₂ 5-F F F A-2943. CH₃ OCHF₂ 5-CH₃ F F A-2944. CH₃ OCHF₂ 5-OCH₃ F F A-2945. CH₃ OCF₃ 3-F F F A-2946. CH₃ OCF₃ 3-CH₃ F F A-2947. CH₃ OCF₃ 3-OCH₃ F F A-2948. CH₃ OCF₃ 5-F F F A-2949. CH₃ OCF₃ 5-CH₃ F F A-2950. CH₃ OCF₃ 5-OCH₃ F F A-2951. OCH₃ F 3-F F F A-2952. OCH₃ F 3-CH₃ F F A-2953. OCH₃ F 3-OCH₃ F F A-2954. OCH₃ F 5-F F F A-2955. OCH₃ F 5-CH₃ F F A-2956. OCH₃ F 5-OCH₃ F F A-2957. OCH₃ CH₃ 3-F F F A-2958. OCH₃ CH₃ 3-CH₃ F F A-2959. OCH₃ CH₃ 3-OCH₃ F F A-2960. OCH₃ CH₃ 5-F F F A-2961. OCH₃ CH₃ 5-CH₃ F F A-2962. OCH₃ CH₃ 5-OCH₃ F F A-2963. OCH₃ OCH₃ 3-F F F A-2964. OCH₃ OCH₃ 3-CH₃ F F A-2965. OCH₃ OCH₃ 3-OCH₃ F F A-2966. OCH₃ OCH₃ 5-F F F A-2967. OCH₃ OCH₃ 5-CH₃ F F A-2968. OCH₃ OCH₃ 5-OCH₃ F F A-2969. OCH₃ CN 3-F F F A-2970. OCH₃ CN 3-CH₃ F F A-2971. OCH₃ CN 3-OCH₃ F F A-2972. OCH₃ CN 5-F F F A-2973. OCH₃ CN 5-CH₃ F F A-2974. OCH₃ CN 5-OCH₃ F F A-2975. OCH₃ CH₂F 3-F F F A-2976. OCH₃ CH₂F 3-CH₃ F F A-2977. OCH₃ CH₂F 3-OCH₃ F F A-2978. OCH₃ CH₂F 5-F F F A-2979. OCH₃ CH₂F 5-CH₃ F F A-2980. OCH₃ CH₂F 5-OCH₃ F F A-2981. OCH₃ CHF₂ 3-F F F A-2982. OCH₃ CHF₂ 3-CH₃ F F A-2983. OCH₃ CHF₂ 3-OCH₃ F F A-2984. OCH₃ CHF₂ 5-F F F A-2985. OCH₃ CHF₂ 5-CH₃ F F A-2986. OCH₃ CHF₂ 5-OCH₃ F F A-2987. OCH₃ CF₃ 3-F F F A-2988. OCH₃ CF₃ 3-CH₃ F F A-2989. OCH₃ CF₃ 3-OCH₃ F F A-2990. OCH₃ CF₃ 5-F F F A-2991. OCH₃ CF₃ 5-CH₃ F F A-2992. OCH₃ CF₃ 5-OCH₃ F F A-2993. OCH₃ OCH₂F 3-F F F A-2994. OCH₃ OCH₂F 3-CH₃ F F A-2995. OCH₃ OCH₂F 3-OCH₃ F F A-2996. OCH₃ OCH₂F 5-F F F A-2997. OCH₃ OCH₂F 5-CH₃ F F A-2998. OCH₃ OCH₂F 5-OCH₃ F F A-2999. OCH₃ OCHF₂ 3-F F F A-3000. OCH₃ OCHF₂ 3-CH₃ F F A-3001. OCH₃ OCHF₂ 3-OCH₃ F F A-3002. OCH₃ OCHF₂ 5-F F F A-3003. OCH₃ OCHF₂ 5-CH₃ F F A-3004. OCH₃ OCHF₂ 5-OCH₃ F F A-3005. OCH₃ OCF₃ 3-F F F A-3006. OCH₃ OCF₃ 3-CH₃ F F A-3007. OCH₃ OCF₃ 3-OCH₃ F F A-3008. OCH₃ OCF₃ 5-F F F A-3009. OCH₃ OCF₃ 5-CH₃ F F A-3010. OCH₃ OCF₃ 5-OCH₃ F F A-3011. CH₂F F 3-F F F A-3012. CH₂F F 3-CH₃ F F A-3013. CH₂F F 3-OCH₃ F F A-3014. CH₂F F 5-F F F A-3015. CH₂F F 5-CH₃ F F A-3016. CH₂F F 5-OCH₃ F F A-3017. CH₂F CH₃ 3-F F F A-3018. CH₂F CH₃ 3-CH₃ F F A-3019. CH₂F CH₃ 3-OCH₃ F F A-3020. CH₂F CH₃ 5-F F F A-3021. CH₂F CH₃ 5-CH₃ F F A-3022. CH₂F CH₃ 5-OCH₃ F F A-3023. CH₂F OCH₃ 3-F F F A-3024. CH₂F OCH₃ 3-CH₃ F F A-3025. CH₂F OCH₃ 3-OCH₃ F F A-3026. CH₂F OCH₃ 5-F F F A-3027. CH₂F OCH₃ 5-CH₃ F F A-3028. CH₂F OCH₃ 5-OCH₃ F F A-3029. CH₂F CN 3-F F F A-3030. CH₂F CN 3-CH₃ F F A-3031. CH₂F CN 3-OCH₃ F F A-3032. CH₂F CN 5-F F F A-3033. CH₂F CN 5-CH₃ F F A-3034. CH₂F CN 5-OCH₃ F F A-3035. CH₂F CH₂F 3-F F F A-3036. CH₂F CH₂F 3-CH₃ F F A-3037. CH₂F CH₂F 3-OCH₃ F F A-3038. CH₂F CH₂F 5-F F F A-3039. CH₂F CH₂F 5-CH₃ F F A-3040. CH₂F CH₂F 5-OCH₃ F F A-3041. CH₂F CHF₂ 3-F F F A-3042. CH₂F CHF₂ 3-CH₃ F F A-3043. CH₂F CHF₂ 3-OCH₃ F F A-3044. CH₂F CHF₂ 5-F F F A-3045. CH₂F CHF₂ 5-CH₃ F F A-3046. CH₂F CHF₂ 5-OCH₃ F F A-3047. CH₂F CF₃ 3-F F F A-3048. CH₂F CF₃ 3-CH₃ F F A-3049. CH₂F CF₃ 3-OCH₃ F F A-3050. CH₂F CF₃ 5-F F F A-3051. CH₂F CF₃ 5-CH₃ F F A-3052. CH₂F CF₃ 5-OCH₃ F F A-3053. CH₂F OCH₂F 3-F F F A-3054. CH₂F OCH₂F 3-CH₃ F F A-3055. CH₂F OCH₂F 3-OCH₃ F F A-3056. CH₂F OCH₂F 5-F F F A-3057. CH₂F OCH₂F 5-CH₃ F F A-3058. CH₂F OCH₂F 5-OCH₃ F F A-3059. CH₂F OCHF₂ 3-F F F A-3060. CH₂F OCHF₂ 3-CH₃ F F A-3061. CH₂F OCHF₂ 3-OCH₃ F F A-3062. CH₂F OCHF₂ 5-F F F A-3063. CH₂F OCHF₂ 5-CH₃ F F A-3064. CH₂F OCHF₂ 5-OCH₃ F F A-3065. CH₂F OCF₃ 3-F F F A-3066. CH₂F OCF₃ 3-CH₃ F F A-3067. CH₂F OCF₃ 3-OCH₃ F F A-3068. CH₂F OCF₃ 5-F F F A-3069. CH₂F OCF₃ 5-CH₃ F F A-3070. CH₂F OCF₃ 5-OCH₃ F F A-3071. CHF₂ F 3-F F F A-3072. CHF₂ F 3-CH₃ F F A-3073. CHF₂ F 3-OCH₃ F F A-3074. CHF₂ F 5-F F F A-3075. CHF₂ F 5-CH₃ F F A-3076. CHF₂ F 5-OCH₃ F F A-3077. CHF₂ CH₃ 3-F F F A-3078. CHF₂ CH₃ 3-CH₃ F F A-3079. CHF₂ CH₃ 3-OCH₃ F F A-3080. CHF₂ CH₃ 5-F F F A-3081. CHF₂ CH₃ 5-CH₃ F F A-3082. CHF₂ CH₃ 5-OCH₃ F F A-3083. CHF₂ OCH₃ 3-F F F A-3084. CHF₂ OCH₃ 3-CH₃ F F A-3085. CHF₂ OCH₃ 3-OCH₃ F F A-3086. CHF₂ OCH₃ 5-F F F A-3087. CHF₂ OCH₃ 5-CH₃ F F A-3088. CHF₂ OCH₃ 5-OCH₃ F F A-3089. CHF₂ CN 3-F F F A-3090. CHF₂ CN 3-CH₃ F F A-3091. CHF₂ CN 3-OCH₃ F F A-3092. CHF₂ CN 5-F F F A-3093. CHF₂ CN 5-CH₃ F F A-3094. CHF₂ CN 5-OCH₃ F F A-3095. CHF₂ CH₂F 3-F F F A-3096. CHF₂ CH₂F 3-CH₃ F F A-3097. CHF₂ CH₂F 3-OCH₃ F F A-3098. CHF₂ CH₂F 5-F F F A-3099. CHF₂ CH₂F 5-CH₃ F F A-3100. CHF₂ CH₂F 5-OCH₃ F F A-3101. CHF₂ CHF₂ 3-F F F A-3102. CHF₂ CHF₂ 3-CH₃ F F A-3103. CHF₂ CHF₂ 3-OCH₃ F F A-3104. CHF₂ CHF₂ 5-F F F A-3105. CHF₂ CHF₂ 5-CH₃ F F A-3106. CHF₂ CHF₂ 5-OCH₃ F F A-3107. CHF₂ CF₃ 3-F F F A-3108. CHF₂ CF₃ 3-CH₃ F F A-3109. CHF₂ CF₃ 3-OCH₃ F F A-3110. CHF₂ CF₃ 5-F F F A-3111. CHF₂ CF₃ 5-CH₃ F F A-3112. CHF₂ CF₃ 5-OCH₃ F F A-3113. CHF₂ OCH₂F 3-F F F A-3114. CHF₂ OCH₂F 3-CH₃ F F A-3115. CHF₂ OCH₂F 3-OCH₃ F F A-3116. CHF₂ OCH₂F 5-F F F A-3117. CHF₂ OCH₂F 5-CH₃ F F A-3118. CHF₂ OCH₂F 5-OCH₃ F F A-3119. CHF₂ OCHF₂ 3-F F F A-3120. CHF₂ OCHF₂ 3-CH₃ F F A-3121. CHF₂ OCHF₂ 3-OCH₃ F F A-3122. CHF₂ OCHF₂ 5-F F F A-3123. CHF₂ OCHF₂ 5-CH₃ F F A-3124. CHF₂ OCHF₂ 5-OCH₃ F F A-3125. CHF₂ OCF₃ 3-F F F A-3126. CHF₂ OCF₃ 3-CH₃ F F A-3127. CHF₂ OCF₃ 3-OCH₃ F F A-3128. CHF₂ OCF₃ 5-F F F A-3129. CHF₂ OCF₃ 5-CH₃ F F A-3130. CHF₂ OCF₃ 5-OCH₃ F F A-3131. CF₃ F 3-F F F A-3132. CF₃ F 3-CH₃ F F A-3133. CF₃ F 3-OCH₃ F F A-3134. CF₃ F 5-F F F A-3135. CF₃ F 5-CH₃ F F A-3136. CF₃ F 5-OCH₃ F F A-3137. CF₃ CH₃ 3-F F F A-3138. CF₃ CH₃ 3-CH₃ F F A-3139. CF₃ CH₃ 3-OCH₃ F F A-3140. CF₃ CH₃ 5-F F F A-3141. CF₃ CH₃ 5-CH₃ F F A-3142. CF₃ CH₃ 5-OCH₃ F F A-3143. CF₃ OCH₃ 3-F F F A-3144. CF₃ OCH₃ 3-CH₃ F F A-3145. CF₃ OCH₃ 3-OCH₃ F F A-3146. CF₃ OCH₃ 5-F F F A-3147. CF₃ OCH₃ 5-CH₃ F F A-3148. CF₃ OCH₃ 5-OCH₃ F F A-3149. CF₃ CN 3-F F F A-3150. CF₃ CN 3-CH₃ F F A-3151. CF₃ CN 3-OCH₃ F F A-3152. CF₃ CN 5-F F F A-3153. CF₃ CN 5-CH₃ F F A-3154. CF₃ CN 5-OCH₃ F F A-3155. CF₃ CH₂F 3-F F F A-3156. CF₃ CH₂F 3-CH₃ F F A-3157. CF₃ CH₂F 3-OCH₃ F F A-3158. CF₃ CH₂F 5-F F F A-3159. CF₃ CH₂F 5-CH₃ F F A-3160. CF₃ CH₂F 5-OCH₃ F F A-3161. CF₃ CHF₂ 3-F F F A-3162. CF₃ CHF₂ 3-CH₃ F F A-3163. CF₃ CHF₂ 3-OCH₃ F F A-3164. CF₃ CHF₂ 5-F F F A-3165. CF₃ CHF₂ 5-CH₃ F F A-3166. CF₃ CHF₂ 5-OCH₃ F F A-3167. CF₃ CF₃ 3-F F F A-3168. CF₃ CF₃ 3-CH₃ F F A-3169. CF₃ CF₃ 3-OCH₃ F F A-3170. CF₃ CF₃ 5-F F F A-3171. CF₃ CF₃ 5-CH₃ F F A-3172. CF₃ CF₃ 5-OCH₃ F F A-3173. CF₃ OCH₂F 3-F F F A-3174. CF₃ OCH₂F 3-CH₃ F F A-3175. CF₃ OCH₂F 3-OCH₃ F F A-3176. CF₃ OCH₂F 5-F F F A-3177. CF₃ OCH₂F 5-CH₃ F F A-3178. CF₃ OCH₂F 5-OCH₃ F F A-3179. CF₃ OCHF₂ 3-F F F A-3180. CF₃ OCHF₂ 3-CH₃ F F A-3181. CF₃ OCHF₂ 3-OCH₃ F F A-3182. CF₃ OCHF₂ 5-F F F A-3183. CF₃ OCHF₂ 5-CH₃ F F A-3184. CF₃ OCHF₂ 5-OCH₃ F F A-3185. CF₃ OCF₃ 3-F F F A-3186. CF₃ OCF₃ 3-CH₃ F F A-3187. CF₃ OCF₃ 3-OCH₃ F F A-3188. CF₃ OCF₃ 5-F F F A-3189. CF₃ OCF₃ 5-CH₃ F F A-3190. CF₃ OCF₃ 5-OCH₃ F F A-3191. OCH₂F F 3-F F F A-3192. OCH₂F F 3-CH₃ F F A-3193. OCH₂F F 3-OCH₃ F F A-3194. OCH₂F F 5-F F F A-3195. OCH₂F F 5-CH₃ F F A-3196. OCH₂F F 5-OCH₃ F F A-3197. OCH₂F CH₃ 3-F F F A-3198. OCH₂F CH₃ 3-CH₃ F F A-3199. OCH₂F CH₃ 3-OCH₃ F F A-3200. OCH₂F CH₃ 5-F F F A-3201. OCH₂F CH₃ 5-CH₃ F F A-3202. OCH₂F CH₃ 5-OCH₃ F F A-3203. OCH₂F OCH₃ 3-F F F A-3204. OCH₂F OCH₃ 3-CH₃ F F A-3205. OCH₂F OCH₃ 3-OCH₃ F F A-3206. OCH₂F OCH₃ 5-F F F A-3207. OCH₂F OCH₃ 5-CH₃ F F A-3208. OCH₂F OCH₃ 5-OCH₃ F F A-3209. OCH₂F CN 3-F F F A-3210. OCH₂F CN 3-CH₃ F F A-3211. OCH₂F CN 3-OCH₃ F F A-3212. OCH₂F CN 5-F F F A-3213. OCH₂F CN 5-CH₃ F F A-3214. OCH₂F CN 5-OCH₃ F F A-3215. OCH₂F CH₂F 3-F F F A-3216. OCH₂F CH₂F 3-CH₃ F F A-3217. OCH₂F CH₂F 3-OCH₃ F F A-3218. OCH₂F CH₂F 5-F F F A-3219. OCH₂F CH₂F 5-CH₃ F F A-3220. OCH₂F CH₂F 5-OCH₃ F F A-3221. OCH₂F CHF₂ 3-F F F A-3222. OCH₂F CHF₂ 3-CH₃ F F A-3223. OCH₂F CHF₂ 3-OCH₃ F F A-3224. OCH₂F CHF₂ 5-F F F A-3225. OCH₂F CHF₂ 5-CH₃ F F A-3226. OCH₂F CHF₂ 5-OCH₃ F F A-3227. OCH₂F CF₃ 3-F F F A-3228. OCH₂F CF₃ 3-CH₃ F F A-3229. OCH₂F CF₃ 3-OCH₃ F F A-3230. OCH₂F CF₃ 5-F F F A-3231. OCH₂F CF₃ 5-CH₃ F F A-3232. OCH₂F CF₃ 5-OCH₃ F F A-3233. OCH₂F OCH₂F 3-F F F A-3234. OCH₂F OCH₂F 3-CH₃ F F A-3235. OCH₂F OCH₂F 3-OCH₃ F F A-3236. OCH₂F OCH₂F 5-F F F A-3237. OCH₂F OCH₂F 5-CH₃ F F A-3238. OCH₂F OCH₂F 5-OCH₃ F F A-3239. OCH₂F OCHF₂ 3-F F F A-3240. OCH₂F OCHF₂ 3-CH₃ F F A-3241. OCH₂F OCHF₂ 3-OCH₃ F F A-3242. OCH₂F OCHF₂ 5-F F F A-3243. OCH₂F OCHF₂ 5-CH₃ F F A-3244. OCH₂F OCHF₂ 5-OCH₃ F F A-3245. OCH₂F OCF₃ 3-F F F A-3246. OCH₂F OCF₃ 3-CH₃ F F A-3247. OCH₂F OCF₃ 3-OCH₃ F F A-3248. OCH₂F OCF₃ 5-F F F A-3249. OCH₂F OCF₃ 5-CH₃ F F A-3250. OCH₂F OCF₃ 5-OCH₃ F F A-3251. OCHF₂ F 3-F F F A-3252. OCHF₂ F 3-CH₃ F F A-3253. OCHF₂ F 3-OCH₃ F F A-3254. OCHF₂ F 5-F F F A-3255. OCHF₂ F 5-CH₃ F F A-3256. OCHF₂ F 5-OCH₃ F F A-3257. OCHF₂ CH₃ 3-F F F A-3258. OCHF₂ CH₃ 3-CH₃ F F A-3259. OCHF₂ CH₃ 3-OCH₃ F F A-3260. OCHF₂ CH₃ 5-F F F A-3261. OCHF₂ CH₃ 5-CH₃ F F A-3262. OCHF₂ CH₃ 5-OCH₃ F F A-3263. OCHF₂ OCH₃ 3-F F F A-3264. OCHF₂ OCH₃ 3-CH₃ F F A-3265. OCHF₂ OCH₃ 3-OCH₃ F F A-3266. OCHF₂ OCH₃ 5-F F F A-3267. OCHF₂ OCH₃ 5-CH₃ F F A-3268. OCHF₂ OCH₃ 5-OCH₃ F F A-3269. OCHF₂ CN 3-F F F A-3270. OCHF₂ CN 3-CH₃ F F A-3271. OCHF₂ CN 3-OCH₃ F F A-3272. OCHF₂ CN 5-F F F A-3273. OCHF₂ CN 5-CH₃ F F A-3274. OCHF₂ CN 5-OCH₃ F F A-3275. OCHF₂ CH₂F 3-F F F A-3276. OCHF₂ CH₂F 3-CH₃ F F A-3277. OCHF₂ CH₂F 3-OCH₃ F F A-3278. OCHF₂ CH₂F 5-F F F A-3279. OCHF₂ CH₂F 5-CH₃ F F A-3280. OCHF₂ CH₂F 5-OCH₃ F F A-3281. OCHF₂ CHF₂ 3-F F F A-3282. OCHF₂ CHF₂ 3-CH₃ F F A-3283. OCHF₂ CHF₂ 3-OCH₃ F F A-3284. OCHF₂ CHF₂ 5-F F F A-3285. OCHF₂ CHF₂ 5-CH₃ F F A-3286. OCHF₂ CHF₂ 5-OCH₃ F F A-3287. OCHF₂ CF₃ 3-F F F A-3288. OCHF₂ CF₃ 3-CH₃ F F A-3289. OCHF₂ CF₃ 3-OCH₃ F F A-3290. OCHF₂ CF₃ 5-F F F A-3291. OCHF₂ CF₃ 5-CH₃ F F A-3292. OCHF₂ CF₃ 5-OCH₃ F F A-3293. OCHF₂ OCH₂F 3-F F F A-3294. OCHF₂ OCH₂F 3-CH₃ F F A-3295. OCHF₂ OCH₂F 3-OCH₃ F F A-3296. OCHF₂ OCH₂F 5-F F F A-3297. OCHF₂ OCH₂F 5-CH₃ F F A-3298. OCHF₂ OCH₂F 5-OCH₃ F F A-3299. OCHF₂ OCHF₂ 3-F F F A-3300. OCHF₂ OCHF₂ 3-CH₃ F F A-3301. OCHF₂ OCHF₂ 3-OCH₃ F F A-3302. OCHF₂ OCHF₂ 5-F F F A-3303. OCHF₂ OCHF₂ 5-CH₃ F F A-3304. OCHF₂ OCHF₂ 5-OCH₃ F F A-3305. OCHF₂ OCF₃ 3-F F F A-3306. OCHF₂ OCF₃ 3-CH₃ F F A-3307. OCHF₂ OCF₃ 3-OCH₃ F F A-3308. OCHF₂ OCF₃ 5-F F F A-3309. OCHF₂ OCF₃ 5-CH₃ F F A-3310. OCHF₂ OCF₃ 5-OCH₃ F F A-3311. OCF₃ F 3-F F F A-3312. OCF₃ F 3-CH₃ F F A-3313. OCF₃ F 3-OCH₃ F F A-3314. OCF₃ F 5-F F F A-3315. OCF₃ F 5-CH₃ F F A-3316. OCF₃ F 5-OCH₃ F F A-3317. OCF₃ CH₃ 3-F F F A-3318. OCF₃ CH₃ 3-CH₃ F F A-3319. OCF₃ CH₃ 3-OCH₃ F F A-3320. OCF₃ CH₃ 5-F F F A-3321. OCF₃ CH₃ 5-CH₃ F F A-3322. OCF₃ CH₃ 5-OCH₃ F F A-3323. OCF₃ OCH₃ 3-F F F A-3324. OCF₃ OCH₃ 3-CH₃ F F A-3325. OCF₃ OCH₃ 3-OCH₃ F F A-3326. OCF₃ OCH₃ 5-F F F A-3327. OCF₃ OCH₃ 5-CH₃ F F A-3328. OCF₃ OCH₃ 5-OCH₃ F F A-3329. OCF₃ CN 3-F F F A-3330. OCF₃ CN 3-CH₃ F F A-3331. OCF₃ CN 3-OCH₃ F F A-3332. OCF₃ CN 5-F F F A-3333. OCF₃ CN 5-CH₃ F F A-3334. OCF₃ CN 5-OCH₃ F F A-3335. OCF₃ CH₂F 3-F F F A-3336. OCF₃ CH₂F 3-CH₃ F F A-3337. OCF₃ CH₂F 3-OCH₃ F F A-3338. OCF₃ CH₂F 5-F F F A-3339. OCF₃ CH₂F 5-CH₃ F F A-3340. OCF₃ CH₂F 5-OCH₃ F F A-3341. OCF₃ CHF₂ 3-F F F A-3342. OCF₃ CHF₂ 3-CH₃ F F A-3343. OCF₃ CHF₂ 3-OCH₃ F F A-3344. OCF₃ CHF₂ 5-F F F A-3345. OCF₃ CHF₂ 5-CH₃ F F A-3346. OCF₃ CHF₂ 5-OCH₃ F F A-3347. OCF₃ CF₃ 3-F F F A-3348. OCF₃ CF₃ 3-CH₃ F F A-3349. OCF₃ CF₃ 3-OCH₃ F F A-3350. OCF₃ CF₃ 5-F F F A-3351. OCF₃ CF₃ 5-CH₃ F F A-3352. OCF₃ CF₃ 5-OCH₃ F F A-3353. OCF₃ OCH₂F 3-F F F A-3354. OCF₃ OCH₂F 3-CH₃ F F A-3355. OCF₃ OCH₂F 3-OCH₃ F F A-3356. OCF₃ OCH₂F 5-F F F A-3357. OCF₃ OCH₂F 5-CH₃ F F A-3358. OCF₃ OCH₂F 5-OCH₃ F F A-3359. OCF₃ OCHF₂ 3-F F F A-3360. OCF₃ OCHF₂ 3-CH₃ F F A-3361. OCF₃ OCHF₂ 3-OCH₃ F F A-3362. OCF₃ OCHF₂ 5-F F F A-3363. OCF₃ OCHF₂ 5-CH₃ F F A-3364. OCF₃ OCHF₂ 5-OCH₃ F F A-3365. OCF₃ OCF₃ 3-F F F A-3366. OCF₃ OCF₃ 3-CH₃ F F A-3367. OCF₃ OCF₃ 3-OCH₃ F F A-3368. OCF₃ OCF₃ 5-F F F A-3369. OCF₃ OCF₃ 5-CH₃ F F A-3370. OCF₃ OCF₃ 5-OCH₃ F F A-3371. H H H Cl F A-3372. F H H Cl F A-3373. CH₃ H H Cl F A-3374. OCH₃ H H Cl F A-3375. CH₂F H H Cl F A-3376. CHF₂ H H Cl F A-3377. CF₃ H H Cl F A-3378. OCH₂F H H Cl F A-3379. OCHF₂ H H Cl F A-3380. OCF₃ H H Cl F A-3381. H F H Cl F A-3382. H CH₃ H Cl F A-3383. H OCH₃ H Cl F A-3384. H CN H Cl F A-3385. H CH₂F H Cl F A-3386. H CHF₂ H Cl F A-3387. H CF₃ H Cl F A-3388. H OCH₂F H Cl F A-3389. H OCHF₂ H Cl F A-3390. H OCF₃ H Cl F A-3391. H H 3-F Cl F A-3392. H H 3-CH₃ Cl F A-3393. H H 3-OCH₃ Cl F A-3394. H H 5-F Cl F A-3395. H H 5-CH₃ Cl F A-3396. H H 5-OCH₃ Cl F A-3397. F F H Cl F A-3398. F CH₃ H Cl F A-3399. F OCH₃ H Cl F A-3400. F CN H Cl F A-3401. F CH₂F H Cl F A-3402. F CHF₂ H Cl F A-3403. F CF₃ H Cl F A-3404. F OCH₂F H Cl F A-3405. F OCHF₂ H Cl F A-3406. F OCF₃ H Cl F A-3407. F H 3-F Cl F A-3408. F H 3-CH₃ Cl F A-3409. F H 3-OCH₃ Cl F A-3410. F H 5-F Cl F A-3411. F H 5-CH₃ Cl F A-3412. F H 5-OCH₃ Cl F A-3413. CH₃ F H Cl F A-3414. CH₃ CH₃ H Cl F A-3415. CH₃ OCH₃ H Cl F A-3416. CH₃ CN H Cl F A-3417. CH₃ CH₂F H Cl F A-3418. CH₃ CHF₂ H Cl F A-3419. CH₃ CF₃ H Cl F A-3420. CH₃ OCH₂F H Cl F A-3421. CH₃ OCHF₂ H Cl F A-3422. CH₃ OCF₃ H Cl F A-3423. CH₃ H 3-F Cl F A-3424. CH₃ H 3-CH₃ Cl F A-3425. CH₃ H 3-OCH₃ Cl F A-3426. CH₃ H 5-F Cl F A-3427. CH₃ H 5-CH₃ Cl F A-3428. CH₃ H 5-OCH₃ Cl F A-3429. OCH₃ F H Cl F A-3430. OCH₃ CH₃ H Cl F A-3431. OCH₃ OCH₃ H Cl F A-3432. OCH₃ CN H Cl F A-3433. OCH₃ CH₂F H Cl F A-3434. OCH₃ CHF₂ H Cl F A-3435. OCH₃ CF₃ H Cl F A-3436. OCH₃ OCH₂F H Cl F A-3437. OCH₃ OCHF₂ H Cl F A-3438. OCH₃ OCF₃ H Cl F A-3439. OCH₃ H 3-F Cl F A-3440. OCH₃ H 3-CH₃ Cl F A-3441. OCH₃ H 3-OCH₃ Cl F A-3442. OCH₃ H 5-F Cl F A-3443. OCH₃ H 5-CH₃ Cl F A-3444. OCH₃ H 5-OCH₃ Cl F A-3445. H F 3-F Cl F A-3446. H F 3-CH₃ Cl F A-3447. H F 3-OCH₃ Cl F A-3448. H F 5-F Cl F A-3449. H F 5-CH₃ Cl F A-3450. H F 5-OCH₃ Cl F A-3451. H CH₃ 3-F Cl F A-3452. H CH₃ 3-CH₃ Cl F A-3453. H CH₃ 3-OCH₃ Cl F A-3454. H CH₃ 5-F Cl F A-3455. H CH₃ 5-CH₃ Cl F A-3456. H CH₃ 5-OCH₃ Cl F A-3457. H OCH₃ 3-F Cl F A-3458. H OCH₃ 3-CH₃ Cl F A-3459. H OCH₃ 3-OCH₃ Cl F A-3460. H OCH₃ 5-F Cl F A-3461. H OCH₃ 5-CH₃ Cl F A-3462. H OCH₃ 5-OCH₃ Cl F A-3463. H CN 3-F Cl F A-3464. H CN 3-CH₃ Cl F A-3465. H CN 3-OCH₃ Cl F A-3466. H CN 5-F Cl F A-3467. H CN 5-CH₃ Cl F A-3468. H CN 5-OCH₃ Cl F A-3469. H CH₂F 3-F Cl F A-3470. H CH₂F 3-CH₃ Cl F A-3471. H CH₂F 3-OCH₃ Cl F A-3472. H CH₂F 5-F Cl F A-3473. H CH₂F 5-CH₃ Cl F A-3474. H CH₂F 5-OCH₃ Cl F A-3475. H CHF₂ 3-F Cl F A-3476. H CHF₂ 3-CH₃ Cl F A-3477. H CHF₂ 3-OCH₃ Cl F A-3478. H CHF₂ 5-F Cl F A-3479. H CHF₂ 5-CH₃ Cl F A-3480. H CHF₂ 5-OCH₃ Cl F A-3481. H CF₃ 3-F Cl F A-3482. H CF₃ 3-CH₃ Cl F A-3483. H CF₃ 3-OCH₃ Cl F A-3484. H CF₃ 5-F Cl F A-3485. H CF₃ 5-CH₃ Cl F A-3486. H CF₃ 5-OCH₃ Cl F A-3487. H OCH₂F 3-F Cl F A-3488. H OCH₂F 3-CH₃ Cl F A-3489. H OCH₂F 3-OCH₃ Cl F A-3490. H OCH₂F 5-F Cl F A-3491. H OCH₂F 5-CH₃ Cl F A-3492. H OCH₂F 5-OCH₃ Cl F A-3493. H OCHF₂ 3-F Cl F A-3494. H OCHF₂ 3-CH₃ Cl F A-3495. H OCHF₂ 3-OCH₃ Cl F A-3496. H OCHF₂ 5-F Cl F A-3497. H OCHF₂ 5-CH₃ Cl F A-3498. H OCHF₂ 5-OCH₃ Cl F A-3499. H OCF₃ 3-F Cl F A-3500. H OCF₃ 3-CH₃ Cl F A-3501. H OCF₃ 3-OCH₃ Cl F A-3502. H OCF₃ 5-F Cl F A-3503. H OCF₃ 5-CH₃ Cl F A-3504. H OCF₃ 5-OCH₃ Cl F A-3505. F F 3-F Cl F A-3506. F F 3-CH₃ Cl F A-3507. F F 3-OCH₃ Cl F A-3508. F F 5-F Cl F A-3509. F F 5-CH₃ Cl F A-3510. F F 5-OCH₃ Cl F A-3511. F CH₃ 3-F Cl F A-3512. F CH₃ 3-CH₃ Cl F A-3513. F CH₃ 3-OCH₃ Cl F A-3514. F CH₃ 5-F Cl F A-3515. F CH₃ 5-CH₃ Cl F A-3516. F CH₃ 5-OCH₃ Cl F A-3517. F OCH₃ 3-F Cl F A-3518. F OCH₃ 3-CH₃ Cl F A-3519. F OCH₃ 3-OCH₃ Cl F A-3520. F OCH₃ 5-F Cl F A-3521. F OCH₃ 5-CH₃ Cl F A-3522. F OCH₃ 5-OCH₃ Cl F A-3523. F CN 3-F Cl F A-3524. F CN 3-CH₃ Cl F A-3525. F CN 3-OCH₃ Cl F A-3526. F CN 5-F Cl F A-3527. F CN 5-CH₃ Cl F A-3528. F CN 5-OCH₃ Cl F A-3529. F CH₂F 3-F Cl F A-3530. F CH₂F 3-CH₃ Cl F A-3531. F CH₂F 3-OCH₃ Cl F A-3532. F CH₂F 5-F Cl F A-3533. F CH₂F 5-CH₃ Cl F A-3534. F CH₂F 5-OCH₃ Cl F A-3535. F CHF₂ 3-F Cl F A-3536. F CHF₂ 3-CH₃ Cl F A-3537. F CHF₂ 3-OCH₃ Cl F A-3538. F CHF₂ 5-F Cl F A-3539. F CHF₂ 5-CH₃ Cl F A-3540. F CHF₂ 5-OCH₃ Cl F A-3541. F CF₃ 3-F Cl F A-3542. F CF₃ 3-CH₃ Cl F A-3543. F CF₃ 3-OCH₃ Cl F A-3544. F CF₃ 5-F Cl F A-3545. F CF₃ 5-CH₃ Cl F A-3546. F CF₃ 5-OCH₃ Cl F A-3547. F OCH₂F 3-F Cl F A-3548. F OCH₂F 3-CH₃ Cl F A-3549. F OCH₂F 3-OCH₃ Cl F A-3550. F OCH₂F 5-F Cl F A-3551. F OCH₂F 5-CH₃ Cl F A-3552. F OCH₂F 5-OCH₃ Cl F A-3553. F OCHF₂ 3-F Cl F A-3554. F OCHF₂ 3-CH₃ Cl F A-3555. F OCHF₂ 3-OCH₃ Cl F A-3556. F OCHF₂ 5-F Cl F A-3557. F OCHF₂ 5-CH₃ Cl F A-3558. F OCHF₂ 5-OCH₃ Cl F A-3559. F OCF₃ 3-F Cl F A-3560. F OCF₃ 3-CH₃ Cl F A-3561. F OCF₃ 3-OCH₃ Cl F A-3562. F OCF₃ 5-F Cl F A-3563. F OCF₃ 5-CH₃ Cl F A-3564. F OCF₃ 5-OCH₃ Cl F A-3565. CH₃ F 3-F Cl F A-3566. CH₃ F 3-CH₃ Cl F A-3567. CH₃ F 3-OCH₃ Cl F A-3568. CH₃ F 5-F Cl F A-3569. CH₃ F 5-CH₃ Cl F A-3570. CH₃ F 5-OCH₃ Cl F A-3571. CH₃ CH₃ 3-F Cl F A-3572. CH₃ CH₃ 3-CH₃ Cl F A-3573. CH₃ CH₃ 3-OCH₃ Cl F A-3574. CH₃ CH₃ 5-F Cl F A-3575. CH₃ CH₃ 5-CH₃ Cl F A-3576. CH₃ CH₃ 5-OCH₃ Cl F A-3577. CH₃ OCH₃ 3-F Cl F A-3578. CH₃ OCH₃ 3-CH₃ Cl F A-3579. CH₃ OCH₃ 3-OCH₃ Cl F A-3580. CH₃ OCH₃ 5-F Cl F A-3581. CH₃ OCH₃ 5-CH₃ Cl F A-3582. CH₃ OCH₃ 5-OCH₃ Cl F A-3583. CH₃ CN 3-F Cl F A-3584. CH₃ CN 3-CH₃ Cl F A-3585. CH₃ CN 3-OCH₃ Cl F A-3586. CH₃ CN 5-F Cl F A-3587. CH₃ CN 5-CH₃ Cl F A-3588. CH₃ CN 5-OCH₃ Cl F A-3589. CH₃ CH₂F 3-F Cl F A-3590. CH₃ CH₂F 3-CH₃ Cl F A-3591. CH₃ CH₂F 3-OCH₃ Cl F A-3592. CH₃ CH₂F 5-F Cl F A-3593. CH₃ CH₂F 5-CH₃ Cl F A-3594. CH₃ CH₂F 5-OCH₃ Cl F A-3595. CH₃ CHF₂ 3-F Cl F A-3596. CH₃ CHF₂ 3-CH₃ Cl F A-3597. CH₃ CHF₂ 3-OCH₃ Cl F A-3598. CH₃ CHF₂ 5-F Cl F A-3599. CH₃ CHF₂ 5-CH₃ Cl F A-3600. CH₃ CHF₂ 5-OCH₃ Cl F A-3601. CH₃ CF₃ 3-F Cl F A-3602. CH₃ CF₃ 3-CH₃ Cl F A-3603. CH₃ CF₃ 3-OCH₃ Cl F A-3604. CH₃ CF₃ 5-F Cl F A-3605. CH₃ CF₃ 5-CH₃ Cl F A-3606. CH₃ CF₃ 5-OCH₃ Cl F A-3607. CH₃ OCH₂F 3-F Cl F A-3608. CH₃ OCH₂F 3-CH₃ Cl F A-3609. CH₃ OCH₂F 3-OCH₃ Cl F A-3610. CH₃ OCH₂F 5-F Cl F A-3611. CH₃ OCH₂F 5-CH₃ Cl F A-3612. CH₃ OCH₂F 5-OCH₃ Cl F A-3613. CH₃ OCHF₂ 3-F Cl F A-3614. CH₃ OCHF₂ 3-CH₃ Cl F A-3615. CH₃ OCHF₂ 3-OCH₃ Cl F A-3616. CH₃ OCHF₂ 5-F Cl F A-3617. CH₃ OCHF₂ 5-CH₃ Cl F A-3618. CH₃ OCHF₂ 5-OCH₃ Cl F A-3619. CH₃ OCF₃ 3-F Cl F A-3620. CH₃ OCF₃ 3-CH₃ Cl F A-3621. CH₃ OCF₃ 3-OCH₃ Cl F A-3622. CH₃ OCF₃ 5-F Cl F A-3623. CH₃ OCF₃ 5-CH₃ Cl F A-3624. CH₃ OCF₃ 5-OCH₃ Cl F A-3625. OCH₃ F 3-F Cl F A-3626. OCH₃ F 3-CH₃ Cl F A-3627. OCH₃ F 3-OCH₃ Cl F A-3628. OCH₃ F 5-F Cl F A-3629. OCH₃ F 5-CH₃ Cl F A-3630. OCH₃ F 5-OCH₃ Cl F A-3631. OCH₃ CH₃ 3-F Cl F A-3632. OCH₃ CH₃ 3-CH₃ Cl F A-3633. OCH₃ CH₃ 3-OCH₃ Cl F A-3634. OCH₃ CH₃ 5-F Cl F A-3635. OCH₃ CH₃ 5-CH₃ Cl F A-3636. OCH₃ CH₃ 5-OCH₃ Cl F A-3637. OCH₃ OCH₃ 3-F Cl F A-3638. OCH₃ OCH₃ 3-CH₃ Cl F A-3639. OCH₃ OCH₃ 3-OCH₃ Cl F A-3640. OCH₃ OCH₃ 5-F Cl F A-3641. OCH₃ OCH₃ 5-CH₃ Cl F A-3642. OCH₃ OCH₃ 5-OCH₃ Cl F A-3643. OCH₃ CN 3-F Cl F A-3644. OCH₃ CN 3-CH₃ Cl F A-3645. OCH₃ CN 3-OCH₃ Cl F A-3646. OCH₃ CN 5-F Cl F A-3647. OCH₃ CN 5-CH₃ Cl F A-3648. OCH₃ CN 5-OCH₃ Cl F A-3649. OCH₃ CH₂F 3-F Cl F A-3650. OCH₃ CH₂F 3-CH₃ Cl F A-3651. OCH₃ CH₂F 3-OCH₃ Cl F A-3652. OCH₃ CH₂F 5-F Cl F A-3653. OCH₃ CH₂F 5-CH₃ Cl F A-3654. OCH₃ CH₂F 5-OCH₃ Cl F A-3655. OCH₃ CHF₂ 3-F Cl F A-3656. OCH₃ CHF₂ 3-CH₃ Cl F A-3657. OCH₃ CHF₂ 3-OCH₃ Cl F A-3658. OCH₃ CHF₂ 5-F Cl F A-3659. OCH₃ CHF₂ 5-CH₃ Cl F A-3660. OCH₃ CHF₂ 5-OCH₃ Cl F A-3661. OCH₃ CF₃ 3-F Cl F A-3662. OCH₃ CF₃ 3-CH₃ Cl F A-3663. OCH₃ CF₃ 3-OCH₃ Cl F A-3664. OCH₃ CF₃ 5-F Cl F A-3665. OCH₃ CF₃ 5-CH₃ Cl F A-3666. OCH₃ CF₃ 5-OCH₃ Cl F A-3667. OCH₃ OCH₂F 3-F Cl F A-3668. OCH₃ OCH₂F 3-CH₃ Cl F A-3669. OCH₃ OCH₂F 3-OCH₃ Cl F A-3670. OCH₃ OCH₂F 5-F Cl F A-3671. OCH₃ OCH₂F 5-CH₃ Cl F A-3672. OCH₃ OCH₂F 5-OCH₃ Cl F A-3673. OCH₃ OCHF₂ 3-F Cl F A-3674. OCH₃ OCHF₂ 3-CH₃ Cl F A-3675. OCH₃ OCHF₂ 3-OCH₃ Cl F A-3676. OCH₃ OCHF₂ 5-F Cl F A-3677. OCH₃ OCHF₂ 5-CH₃ Cl F A-3678. OCH₃ OCHF₂ 5-OCH₃ Cl F A-3679. OCH₃ OCF₃ 3-F Cl F A-3680. OCH₃ OCF₃ 3-CH₃ Cl F A-3681. OCH₃ OCF₃ 3-OCH₃ Cl F A-3682. OCH₃ OCF₃ 5-F Cl F A-3683. OCH₃ OCF₃ 5-CH₃ Cl F A-3684. OCH₃ OCF₃ 5-OCH₃ Cl F A-3685. CH₂F F 3-F Cl F A-3686. CH₂F F 3-CH₃ Cl F A-3687. CH₂F F 3-OCH₃ Cl F A-3688. CH₂F F 5-F Cl F A-3689. CH₂F F 5-CH₃ Cl F A-3690. CH₂F F 5-OCH₃ Cl F A-3691. CH₂F CH₃ 3-F Cl F A-3692. CH₂F CH₃ 3-CH₃ Cl F A-3693. CH₂F CH₃ 3-OCH₃ Cl F A-3694. CH₂F CH₃ 5-F Cl F A-3695. CH₂F CH₃ 5-CH₃ Cl F A-3696. CH₂F CH₃ 5-OCH₃ Cl F A-3697. CH₂F OCH₃ 3-F Cl F A-3698. CH₂F OCH₃ 3-CH₃ Cl F A-3699. CH₂F OCH₃ 3-OCH₃ Cl F A-3700. CH₂F OCH₃ 5-F Cl F A-3701. CH₂F OCH₃ 5-CH₃ Cl F A-3702. CH₂F OCH₃ 5-OCH₃ Cl F A-3703. CH₂F CN 3-F Cl F A-3704. CH₂F CN 3-CH₃ Cl F A-3705. CH₂F CN 3-OCH₃ Cl F A-3706. CH₂F CN 5-F Cl F A-3707. CH₂F CN 5-CH₃ Cl F A-3708. CH₂F CN 5-OCH₃ Cl F A-3709. CH₂F CH₂F 3-F Cl F A-3710. CH₂F CH₂F 3-CH₃ Cl F A-3711. CH₂F CH₂F 3-OCH₃ Cl F A-3712. CH₂F CH₂F 5-F Cl F A-3713. CH₂F CH₂F 5-CH₃ Cl F A-3714. CH₂F CH₂F 5-OCH₃ Cl F A-3715. CH₂F CHF₂ 3-F Cl F A-3716. CH₂F CHF₂ 3-CH₃ Cl F A-3717. CH₂F CHF₂ 3-OCH₃ Cl F A-3718. CH₂F CHF₂ 5-F Cl F A-3719. CH₂F CHF₂ 5-CH₃ Cl F A-3720. CH₂F CHF₂ 5-OCH₃ Cl F A-3721. CH₂F CF₃ 3-F Cl F A-3722. CH₂F CF₃ 3-CH₃ Cl F A-3723. CH₂F CF₃ 3-OCH₃ Cl F A-3724. CH₂F CF₃ 5-F Cl F A-3725. CH₂F CF₃ 5-CH₃ Cl F A-3726. CH₂F CF₃ 5-OCH₃ Cl F A-3727. CH₂F OCH₂F 3-F Cl F A-3728. CH₂F OCH₂F 3-CH₃ Cl F A-3729. CH₂F OCH₂F 3-OCH₃ Cl F A-3730. CH₂F OCH₂F 5-F Cl F A-3731. CH₂F OCH₂F 5-CH₃ Cl F A-3732. CH₂F OCH₂F 5-OCH₃ Cl F A-3733. CH₂F OCHF₂ 3-F Cl F A-3734. CH₂F OCHF₂ 3-CH₃ Cl F A-3735. CH₂F OCHF₂ 3-OCH₃ Cl F A-3736. CH₂F OCHF₂ 5-F Cl F A-3737. CH₂F OCHF₂ 5-CH₃ Cl F A-3738. CH₂F OCHF₂ 5-OCH₃ Cl F A-3739. CH₂F OCF₃ 3-F Cl F A-3740. CH₂F OCF₃ 3-CH₃ Cl F A-3741. CH₂F OCF₃ 3-OCH₃ Cl F A-3742. CH₂F OCF₃ 5-F Cl F A-3743. CH₂F OCF₃ 5-CH₃ Cl F A-3744. CH₂F OCF₃ 5-OCH₃ Cl F A-3745. CHF₂ F 3-F Cl F A-3746. CHF₂ F 3-CH₃ Cl F A-3747. CHF₂ F 3-OCH₃ Cl F A-3748. CHF₂ F 5-F Cl F A-3749. CHF₂ F 5-CH₃ Cl F A-3750. CHF₂ F 5-OCH₃ Cl F A-3751. CHF₂ CH₃ 3-F Cl F A-3752. CHF₂ CH₃ 3-CH₃ Cl F A-3753. CHF₂ CH₃ 3-OCH₃ Cl F A-3754. CHF₂ CH₃ 5-F Cl F A-3755. CHF₂ CH₃ 5-CH₃ Cl F A-3756. CHF₂ CH₃ 5-OCH₃ Cl F A-3757. CHF₂ OCH₃ 3-F Cl F A-3758. CHF₂ OCH₃ 3-CH₃ Cl F A-3759. CHF₂ OCH₃ 3-OCH₃ Cl F A-3760. CHF₂ OCH₃ 5-F Cl F A-3761. CHF₂ OCH₃ 5-CH₃ Cl F A-3762. CHF₂ OCH₃ 5-OCH₃ Cl F A-3763. CHF₂ CN 3-F Cl F A-3764. CHF₂ CN 3-CH₃ Cl F A-3765. CHF₂ CN 3-OCH₃ Cl F A-3766. CHF₂ CN 5-F Cl F A-3767. CHF₂ CN 5-CH₃ Cl F A-3768. CHF₂ CN 5-OCH₃ Cl F A-3769. CHF₂ CH₂F 3-F Cl F A-3770. CHF₂ CH₂F 3-CH₃ Cl F A-3771. CHF₂ CH₂F 3-OCH₃ Cl F A-3772. CHF₂ CH₂F 5-F Cl F A-3773. CHF₂ CH₂F 5-CH₃ Cl F A-3774. CHF₂ CH₂F 5-OCH₃ Cl F A-3775. CHF₂ CHF₂ 3-F Cl F A-3776. CHF₂ CHF₂ 3-CH₃ Cl F A-3777. CHF₂ CHF₂ 3-OCH₃ Cl F A-3778. CHF₂ CHF₂ 5-F Cl F A-3779. CHF₂ CHF₂ 5-CH₃ Cl F A-3780. CHF₂ CHF₂ 5-OCH₃ Cl F A-3781. CHF₂ CF₃ 3-F Cl F A-3782. CHF₂ CF₃ 3-CH₃ Cl F A-3783. CHF₂ CF₃ 3-OCH₃ Cl F A-3784. CHF₂ CF₃ 5-F Cl F A-3785. CHF₂ CF₃ 5-CH₃ Cl F A-3786. CHF₂ CF₃ 5-OCH₃ Cl F A-3787. CHF₂ OCH₂F 3-F Cl F A-3788. CHF₂ OCH₂F 3-CH₃ Cl F A-3789. CHF₂ OCH₂F 3-OCH₃ Cl F A-3790. CHF₂ OCH₂F 5-F Cl F A-3791. CHF₂ OCH₂F 5-CH₃ Cl F A-3792. CHF₂ OCH₂F 5-OCH₃ Cl F A-3793. CHF₂ OCHF₂ 3-F Cl F A-3794. CHF₂ OCHF₂ 3-CH₃ Cl F A-3795. CHF₂ OCHF₂ 3-OCH₃ Cl F A-3796. CHF₂ OCHF₂ 5-F Cl F A-3797. CHF₂ OCHF₂ 5-CH₃ Cl F A-3798. CHF₂ OCHF₂ 5-OCH₃ Cl F A-3799. CHF₂ OCF₃ 3-F Cl F A-3800. CHF₂ OCF₃ 3-CH₃ Cl F A-3801. CHF₂ OCF₃ 3-OCH₃ Cl F A-3802. CHF₂ OCF₃ 5-F Cl F A-3803. CHF₂ OCF₃ 5-CH₃ Cl F A-3804. CHF₂ OCF₃ 5-OCH₃ Cl F A-3805. CF₃ F 3-F Cl F A-3806. CF₃ F 3-CH₃ Cl F A-3807. CF₃ F 3-OCH₃ Cl F A-3808. CF₃ F 5-F Cl F A-3809. CF₃ F 5-CH₃ Cl F A-3810. CF₃ F 5-OCH₃ Cl F A-3811. CF₃ CH₃ 3-F Cl F A-3812. CF₃ CH₃ 3-CH₃ Cl F A-3813. CF₃ CH₃ 3-OCH₃ Cl F A-3814. CF₃ CH₃ 5-F Cl F A-3815. CF₃ CH₃ 5-CH₃ Cl F A-3816. CF₃ CH₃ 5-OCH₃ Cl F A-3817. CF₃ OCH₃ 3-F Cl F A-3818. CF₃ OCH₃ 3-CH₃ Cl F A-3819. CF₃ OCH₃ 3-OCH₃ Cl F A-3820. CF₃ OCH₃ 5-F Cl F A-3821. CF₃ OCH₃ 5-CH₃ Cl F A-3822. CF₃ OCH₃ 5-OCH₃ Cl F A-3823. CF₃ CN 3-F Cl F A-3824. CF₃ CN 3-CH₃ Cl F A-3825. CF₃ CN 3-OCH₃ Cl F A-3826. CF₃ CN 5-F Cl F A-3827. CF₃ CN 5-CH₃ Cl F A-3828. CF₃ CN 5-OCH₃ Cl F A-3829. CF₃ CH₂F 3-F Cl F A-3830. CF₃ CH₂F 3-CH₃ Cl F A-3831. CF₃ CH₂F 3-OCH₃ Cl F A-3832. CF₃ CH₂F 5-F Cl F A-3833. CF₃ CH₂F 5-CH₃ Cl F A-3834. CF₃ CH₂F 5-OCH₃ Cl F A-3835. CF₃ CHF₂ 3-F Cl F A-3836. CF₃ CHF₂ 3-CH₃ Cl F A-3837. CF₃ CHF₂ 3-OCH₃ Cl F A-3838. CF₃ CHF₂ 5-F Cl F A-3839. CF₃ CHF₂ 5-CH₃ Cl F A-3840. CF₃ CHF₂ 5-OCH₃ Cl F A-3841. CF₃ CF₃ 3-F Cl F A-3842. CF₃ CF₃ 3-CH₃ Cl F A-3843. CF₃ CF₃ 3-OCH₃ Cl F A-3844. CF₃ CF₃ 5-F Cl F A-3845. CF₃ CF₃ 5-CH₃ Cl F A-3846. CF₃ CF₃ 5-OCH₃ Cl F A-3847. CF₃ OCH₂F 3-F Cl F A-3848. CF₃ OCH₂F 3-CH₃ Cl F A-3849. CF₃ OCH₂F 3-OCH₃ Cl F A-3850. CF₃ OCH₂F 5-F Cl F A-3851. CF₃ OCH₂F 5-CH₃ Cl F A-3852. CF₃ OCH₂F 5-OCH₃ Cl F A-3853. CF₃ OCHF₂ 3-F Cl F A-3854. CF₃ OCHF₂ 3-CH₃ Cl F A-3855. CF₃ OCHF₂ 3-OCH₃ Cl F A-3856. CF₃ OCHF₂ 5-F Cl F A-3857. CF₃ OCHF₂ 5-CH₃ Cl F A-3858. CF₃ OCHF₂ 5-OCH₃ Cl F A-3859. CF₃ OCF₃ 3-F Cl F A-3860. CF₃ OCF₃ 3-CH₃ Cl F A-3861. CF₃ OCF₃ 3-OCH₃ Cl F A-3862. CF₃ OCF₃ 5-F Cl F A-3863. CF₃ OCF₃ 5-CH₃ Cl F A-3864. CF₃ OCF₃ 5-OCH₃ Cl F A-3865. OCH₂F F 3-F Cl F A-3866. OCH₂F F 3-CH₃ Cl F A-3867. OCH₂F F 3-OCH₃ Cl F A-3868. OCH₂F F 5-F Cl F A-3869. OCH₂F F 5-CH₃ Cl F A-3870. OCH₂F F 5-OCH₃ Cl F A-3871. OCH₂F CH₃ 3-F Cl F A-3872. OCH₂F CH₃ 3-CH₃ Cl F A-3873. OCH₂F CH₃ 3-OCH₃ Cl F A-3874. OCH₂F CH₃ 5-F Cl F A-3875. OCH₂F CH₃ 5-CH₃ Cl F A-3876. OCH₂F CH₃ 5-OCH₃ Cl F A-3877. OCH₂F OCH₃ 3-F Cl F A-3878. OCH₂F OCH₃ 3-CH₃ Cl F A-3879. OCH₂F OCH₃ 3-OCH₃ Cl F A-3880. OCH₂F OCH₃ 5-F Cl F A-3881. OCH₂F OCH₃ 5-CH₃ Cl F A-3882. OCH₂F OCH₃ 5-OCH₃ Cl F A-3883. OCH₂F CN 3-F Cl F A-3884. OCH₂F CN 3-CH₃ Cl F A-3885. OCH₂F CN 3-OCH₃ Cl F A-3886. OCH₂F CN 5-F Cl F A-3887. OCH₂F CN 5-CH₃ Cl F A-3888. OCH₂F CN 5-OCH₃ Cl F A-3889. OCH₂F CH₂F 3-F Cl F A-3890. OCH₂F CH₂F 3-CH₃ Cl F A-3891. OCH₂F CH₂F 3-OCH₃ Cl F A-3892. OCH₂F CH₂F 5-F Cl F A-3893. OCH₂F CH₂F 5-CH₃ Cl F A-3894. OCH₂F CH₂F 5-OCH₃ Cl F A-3895. OCH₂F CHF₂ 3-F Cl F A-3896. OCH₂F CHF₂ 3-CH₃ Cl F A-3897. OCH₂F CHF₂ 3-OCH₃ Cl F A-3898. OCH₂F CHF₂ 5-F Cl F A-3899. OCH₂F CHF₂ 5-CH₃ Cl F A-3900. OCH₂F CHF₂ 5-OCH₃ Cl F A-3901. OCH₂F CF₃ 3-F Cl F A-3902. OCH₂F CF₃ 3-CH₃ Cl F A-3903. OCH₂F CF₃ 3-OCH₃ Cl F A-3904. OCH₂F CF₃ 5-F Cl F A-3905. OCH₂F CF₃ 5-CH₃ Cl F A-3906. OCH₂F CF₃ 5-OCH₃ Cl F A-3907. OCH₂F OCH₂F 3-F Cl F A-3908. OCH₂F OCH₂F 3-CH₃ Cl F A-3909. OCH₂F OCH₂F 3-OCH₃ Cl F A-3910. OCH₂F OCH₂F 5-F Cl F A-3911. OCH₂F OCH₂F 5-CH₃ Cl F A-3912. OCH₂F OCH₂F 5-OCH₃ Cl F A-3913. OCH₂F OCHF₂ 3-F Cl F A-3914. OCH₂F OCHF₂ 3-CH₃ Cl F A-3915. OCH₂F OCHF₂ 3-OCH₃ Cl F A-3916. OCH₂F OCHF₂ 5-F Cl F A-3917. OCH₂F OCHF₂ 5-CH₃ Cl F A-3918. OCH₂F OCHF₂ 5-OCH₃ Cl F A-3919. OCH₂F OCF₃ 3-F Cl F A-3920. OCH₂F OCF₃ 3-CH₃ Cl F A-3921. OCH₂F OCF₃ 3-OCH₃ Cl F A-3922. OCH₂F OCF₃ 5-F Cl F A-3923. OCH₂F OCF₃ 5-CH₃ Cl F A-3924. OCH₂F OCF₃ 5-OCH₃ Cl F A-3925. OCHF₂ F 3-F Cl F A-3926. OCHF₂ F 3-CH₃ Cl F A-3927. OCHF₂ F 3-OCH₃ Cl F A-3928. OCHF₂ F 5-F Cl F A-3929. OCHF₂ F 5-CH₃ Cl F A-3930. OCHF₂ F 5-OCH₃ Cl F A-3931. OCHF₂ CH₃ 3-F Cl F A-3932. OCHF₂ CH₃ 3-CH₃ Cl F A-3933. OCHF₂ CH₃ 3-OCH₃ Cl F A-3934. OCHF₂ CH₃ 5-F Cl F A-3935. OCHF₂ CH₃ 5-CH₃ Cl F A-3936. OCHF₂ CH₃ 5-OCH₃ Cl F A-3937. OCHF₂ OCH₃ 3-F Cl F A-3938. OCHF₂ OCH₃ 3-CH₃ Cl F A-3939. OCHF₂ OCH₃ 3-OCH₃ Cl F A-3940. OCHF₂ OCH₃ 5-F Cl F A-3941. OCHF₂ OCH₃ 5-CH₃ Cl F A-3942. OCHF₂ OCH₃ 5-OCH₃ Cl F A-3943. OCHF₂ CN 3-F Cl F A-3944. OCHF₂ CN 3-CH₃ Cl F A-3945. OCHF₂ CN 3-OCH₃ Cl F A-3946. OCHF₂ CN 5-F Cl F A-3947. OCHF₂ CN 5-CH₃ Cl F A-3948. OCHF₂ CN 5-OCH₃ Cl F A-3949. OCHF₂ CH₂F 3-F Cl F A-3950. OCHF₂ CH₂F 3-CH₃ Cl F A-3951. OCHF₂ CH₂F 3-OCH₃ Cl F A-3952. OCHF₂ CH₂F 5-F Cl F A-3953. OCHF₂ CH₂F 5-CH₃ Cl F A-3954. OCHF₂ CH₂F 5-OCH₃ Cl F A-3955. OCHF₂ CHF₂ 3-F Cl F A-3956. OCHF₂ CHF₂ 3-CH₃ Cl F A-3957. OCHF₂ CHF₂ 3-OCH₃ Cl F A-3958. OCHF₂ CHF₂ 5-F Cl F A-3959. OCHF₂ CHF₂ 5-CH₃ Cl F A-3960. OCHF₂ CHF₂ 5-OCH₃ Cl F A-3961. OCHF₂ CF₃ 3-F Cl F A-3962. OCHF₂ CF₃ 3-CH₃ Cl F A-3963. OCHF₂ CF₃ 3-OCH₃ Cl F A-3964. OCHF₂ CF₃ 5-F Cl F A-3965. OCHF₂ CF₃ 5-CH₃ Cl F A-3966. OCHF₂ CF₃ 5-OCH₃ Cl F A-3967. OCHF₂ OCH₂F 3-F Cl F A-3968. OCHF₂ OCH₂F 3-CH₃ Cl F A-3969. OCHF₂ OCH₂F 3-OCH₃ Cl F A-3970. OCHF₂ OCH₂F 5-F Cl F A-3971. OCHF₂ OCH₂F 5-CH₃ Cl F A-3972. OCHF₂ OCH₂F 5-OCH₃ Cl F A-3973. OCHF₂ OCHF₂ 3-F Cl F A-3974. OCHF₂ OCHF₂ 3-CH₃ Cl F A-3975. OCHF₂ OCHF₂ 3-OCH₃ Cl F A-3976. OCHF₂ OCHF₂ 5-F Cl F A-3977. OCHF₂ OCHF₂ 5-CH₃ Cl F A-3978. OCHF₂ OCHF₂ 5-OCH₃ Cl F A-3979. OCHF₂ OCF₃ 3-F Cl F A-3980. OCHF₂ OCF₃ 3-CH₃ Cl F A-3981. OCHF₂ OCF₃ 3-OCH₃ Cl F A-3982. OCHF₂ OCF₃ 5-F Cl F A-3983. OCHF₂ OCF₃ 5-CH₃ Cl F A-3984. OCHF₂ OCF₃ 5-OCH₃ Cl F A-3985. OCF₃ F 3-F Cl F A-3986. OCF₃ F 3-CH₃ Cl F A-3987. OCF₃ F 3-OCH₃ Cl F A-3988. OCF₃ F 5-F Cl F A-3989. OCF₃ F 5-CH₃ Cl F A-3990. OCF₃ F 5-OCH₃ Cl F A-3991. OCF₃ CH₃ 3-F Cl F A-3992. OCF₃ CH₃ 3-CH₃ Cl F A-3993. OCF₃ CH₃ 3-OCH₃ Cl F A-3994. OCF₃ CH₃ 5-F Cl F A-3995. OCF₃ CH₃ 5-CH₃ Cl F A-3996. OCF₃ CH₃ 5-OCH₃ Cl F A-3997. OCF₃ OCH₃ 3-F Cl F A-3998. OCF₃ OCH₃ 3-CH₃ Cl F A-3999. OCF₃ OCH₃ 3-OCH₃ Cl F A-4000. OCF₃ OCH₃ 5-F Cl F A-4001. OCF₃ OCH₃ 5-CH₃ Cl F A-4002. OCF₃ OCH₃ 5-OCH₃ Cl F A-4003. OCF₃ CN 3-F Cl F A-4004. OCF₃ CN 3-CH₃ Cl F A-4005. OCF₃ CN 3-OCH₃ Cl F A-4006. OCF₃ CN 5-F Cl F A-4007. OCF₃ CN 5-CH₃ Cl F A-4008. OCF₃ CN 5-OCH₃ Cl F A-4009. OCF₃ CH₂F 3-F Cl F A-4010. OCF₃ CH₂F 3-CH₃ Cl F A-4011. OCF₃ CH₂F 3-OCH₃ Cl F A-4012. OCF₃ CH₂F 5-F Cl F A-4013. OCF₃ CH₂F 5-CH₃ Cl F A-4014. OCF₃ CH₂F 5-OCH₃ Cl F A-4015. OCF₃ CHF₂ 3-F Cl F A-4016. OCF₃ CHF₂ 3-CH₃ Cl F A-4017. OCF₃ CHF₂ 3-OCH₃ Cl F A-4018. OCF₃ CHF₂ 5-F Cl F A-4019. OCF₃ CHF₂ 5-CH₃ Cl F A-4020. OCF₃ CHF₂ 5-OCH₃ Cl F A-4021. OCF₃ CF₃ 3-F Cl F A-4022. OCF₃ CF₃ 3-CH₃ Cl F A-4023. OCF₃ CF₃ 3-OCH₃ Cl F A-4024. OCF₃ CF₃ 5-F Cl F A-4025. OCF₃ CF₃ 5-CH₃ Cl F A-4026. OCF₃ CF₃ 5-OCH₃ Cl F A-4027. OCF₃ OCH₂F 3-F Cl F A-4028. OCF₃ OCH₂F 3-CH₃ Cl F A-4029. OCF₃ OCH₂F 3-OCH₃ Cl F A-4030. OCF₃ OCH₂F 5-F Cl F A-4031. OCF₃ OCH₂F 5-CH₃ Cl F A-4032. OCF₃ OCH₂F 5-OCH₃ Cl F A-4033. OCF₃ OCHF₂ 3-F Cl F A-4034. OCF₃ OCHF₂ 3-CH₃ Cl F A-4035. OCF₃ OCHF₂ 3-OCH₃ Cl F A-4036. OCF₃ OCHF₂ 5-F Cl F A-4037. OCF₃ OCHF₂ 5-CH₃ Cl F A-4038. OCF₃ OCHF₂ 5-OCH₃ Cl F A-4039. OCF₃ OCF₃ 3-F Cl F A-4040. OCF₃ OCF₃ 3-CH₃ Cl F A-4041. OCF₃ OCF₃ 3-OCH₃ Cl F A-4042. OCF₃ OCF₃ 5-F Cl F A-4043. OCF₃ OCF₃ 5-CH₃ Cl F A-4044. OCF₃ OCF₃ 5-OCH₃ Cl F

TABLE B Example No. R² R³ R⁶ R⁷ B-1. H H CN H B-2. F H CN H B-3. CH₃ H CN H B-4. OCH₃ H CN H B-5. CN H CN H B-6. CH₂F H CN H B-7. CHF₂ H CN H B-8. CF₃ H CN H B-9. OCH₂F H CN H B-10. OCHF₂ H CN H B-11. OCF₃ H CN H B-12. H 3-F CN H B-13. H 3-CH₃ CN H B-14. H 3-OCH₃ CN H B-15. H 5-F CN H B-16. H 5-CH₃ CN H B-17. H 5-OCH₃ CN H B-18. H 6-F CN H B-19. H 6-CH₃ CN H B-20. H 6-OCH₃ CN H B-21. F 3-F CN H B-22. F 3-CH₃ CN H B-23. F 3-OCH₃ CN H B-24. F 5-F CN H B-25. F 5-CH₃ CN H B-26. F 5-OCH₃ CN H B-27. F 6-F CN H B-28. F 6-CH₃ CN H B-29. F 6-OCH₃ CN H B-30. CH₃ 3-F CN H B-31. CH₃ 3-CH₃ CN H B-32. CH₃ 3-OCH₃ CN H B-33. CH₃ 5-F CN H B-34. CH₃ 5-CH₃ CN H B-35. CH₃ 5-OCH₃ CN H B-36. CH₃ 6-F CN H B-37. CH₃ 6-CH₃ CN H B-38. CH₃ 6-OCH₃ CN H B-39. OCH₃ 3-F CN H B-40. OCH₃ 3-CH₃ CN H B-41. OCH₃ 3-OCH₃ CN H B-42. OCH₃ 5-F CN H B-43. OCH₃ 5-CH₃ CN H B-44. OCH₃ 5-OCH₃ CN H B-45. OCH₃ 6-F CN H B-46. OCH₃ 6-CH₃ CN H B-47. OCH₃ 6-OCH₃ CN H B-48. CN 3-F CN H B-49. CN 3-CH₃ CN H B-50. CN 3-OCH₃ CN H B-51. CN 5-F CN H B-52. CN 5-CH₃ CN H B-53. CN 5-OCH₃ CN H B-54. CN 6-F CN H B-55. CN 6-CH₃ CN H B-56. CN 6-OCH₃ CN H B-57. CH₂F 3-F CN H B-58. CH₂F 3-CH₃ CN H B-59. CH₂F 3-OCH₃ CN H B-60. CH₂F 5-F CN H B-61. CH₂F 5-CH₃ CN H B-62. CH₂F 5-OCH₃ CN H B-63. CH₂F 6-F CN H B-64. CH₂F 6-CH₃ CN H B-65. CH₂F 6-OCH₃ CN H B-66. CHF₂ 3-F CN H B-67. CHF₂ 3-CH₃ CN H B-68. CHF₂ 3-OCH₃ CN H B-69. CHF₂ 5-F CN H B-70. CHF₂ 5-CH₃ CN H B-71. CHF₂ 5-OCH₃ CN H B-72. CHF₂ 6-F CN H B-73. CHF₂ 6-CH₃ CN H B-74. CHF₂ 6-OCH₃ CN H B-75. CF₃ 3-F CN H B-76. CF₃ 3-CH₃ CN H B-77. CF₃ 3-OCH₃ CN H B-78. CF₃ 5-F CN H B-79. CF₃ 5-CH₃ CN H B-80. CF₃ 5-OCH₃ CN H B-81. CF₃ 6-F CN H B-82. CF₃ 6-CH₃ CN H B-83. CF₃ 6-OCH₃ CN H B-84. OCH₂F 3-F CN H B-85. OCH₂F 3-CH₃ CN H B-86. OCH₂F 3-OCH₃ CN H B-87. OCH₂F 5-F CN H B-88. OCH₂F 5-CH₃ CN H B-89. OCH₂F 5-OCH₃ CN H B-90. OCH₂F 6-F CN H B-91. OCH₂F 6-CH₃ CN H B-92. OCH₂F 6-OCH₃ CN H B-93. OCHF₂ 3-F CN H B-94. OCHF₂ 3-CH₃ CN H B-95. OCHF₂ 3-OCH₃ CN H B-96. OCHF₂ 5-F CN H B-97. OCHF₂ 5-CH₃ CN H B-98. OCHF₂ 5-OCH₃ CN H B-99. OCHF₂ 6-F CN H B-100. OCHF₂ 6-CH₃ CN H B-101. OCHF₂ 6-OCH₃ CN H B-102. OCF₃ 3-F CN H B-103. OCF₃ 3-CH₃ CN H B-104. OCF₃ 3-OCH₃ CN H B-105. OCF₃ 5-F CN H B-106. OCF₃ 5-CH₃ CN H B-107. OCF₃ 5-OCH₃ CN H B-108. OCF₃ 6-F CN H B-109. OCF₃ 6-CH₃ CN H B-110. OCF₃ 6-OCH₃ CN H B-111. H H F H B-112. F H F H B-113. CH₃ H F H B-114. OCH₃ H F H B-115. CN H F H B-116. CH₂F H F H B-117. CHF₂ H F H B-118. CF₃ H F H B-119. OCH₂F H F H B-120. OCHF₂ H F H B-121. OCF₃ H F H B-122. H 3-F F H B-123. H 3-CH₃ F H B-124. H 3-OCH₃ F H B-125. H 5-F F H B-126. H 5-CH₃ F H B-127. H 5-OCH₃ F H B-128. H 6-F F H B-129. H 6-CH₃ F H B-130. H 6-OCH₃ F H B-131. F 3-F F H B-132. F 3-CH₃ F H B-133. F 3-OCH₃ F H B-134. F 5-F F H B-135. F 5-CH₃ F H B-136. F 5-OCH₃ F H B-137. F 6-F F H B-138. F 6-CH₃ F H B-139. F 6-OCH₃ F H B-140. CH₃ 3-F F H B-141. CH₃ 3-CH₃ F H B-142. CH₃ 3-OCH₃ F H B-143. CH₃ 5-F F H B-144. CH₃ 5-CH₃ F H B-145. CH₃ 5-OCH₃ F H B-146. CH₃ 6-F F H B-147. CH₃ 6-CH₃ F H B-148. CH₃ 6-OCH₃ F H B-149. OCH₃ 3-F F H B-150. OCH₃ 3-CH₃ F H B-151. OCH₃ 3-OCH₃ F H B-152. OCH₃ 5-F F H B-153. OCH₃ 5-CH₃ F H B-154. OCH₃ 5-OCH₃ F H B-155. OCH₃ 6-F F H B-156. OCH₃ 6-CH₃ F H B-157. OCH₃ 6-OCH₃ F H B-158. CN 3-F F H B-159. CN 3-CH₃ F H B-160. CN 3-OCH₃ F H B-161. CN 5-F F H B-162. CN 5-CH₃ F H B-163. CN 5-OCH₃ F H B-164. CN 6-F F H B-165. CN 6-CH₃ F H B-166. CN 6-OCH₃ F H B-167. CH₂F 3-F F H B-168. CH₂F 3-CH₃ F H B-169. CH₂F 3-OCH₃ F H B-170. CH₂F 5-F F H B-171. CH₂F 5-CH₃ F H B-172. CH₂F 5-OCH₃ F H B-173. CH₂F 6-F F H B-174. CH₂F 6-CH₃ F H B-175. CH₂F 6-OCH₃ F H B-176. CHF₂ 3-F F H B-177. CHF₂ 3-CH₃ F H B-178. CHF₂ 3-OCH₃ F H B-179. CHF₂ 5-F F H B-180. CHF₂ 5-CH₃ F H B-181. CHF₂ 5-OCH₃ F H B-182. CHF₂ 6-F F H B-183. CHF₂ 6-CH₃ F H B-184. CHF₂ 6-OCH₃ F H B-185. CF₃ 3-F F H B-186. CF₃ 3-CH₃ F H B-187. CF₃ 3-OCH₃ F H B-188. CF₃ 5-F F H B-189. CF₃ 5-CH₃ F H B-190. CF₃ 5-OCH₃ F H B-191. CF₃ 6-F F H B-192. CF₃ 6-CH₃ F H B-193. CF₃ 6-OCH₃ F H B-194. OCH₂F 3-F F H B-195. OCH₂F 3-CH₃ F H B-196. OCH₂F 3-OCH₃ F H B-197. OCH₂F 5-F F H B-198. OCH₂F 5-CH₃ F H B-199. OCH₂F 5-OCH₃ F H B-200. OCH₂F 6-F F H B-201. OCH₂F 6-CH₃ F H B-202. OCH₂F 6-OCH₃ F H B-203. OCHF₂ 3-F F H B-204. OCHF₂ 3-CH₃ F H B-205. OCHF₂ 3-OCH₃ F H B-206. OCHF₂ 5-F F H B-207. OCHF₂ 5-CH₃ F H B-208. OCHF₂ 5-OCH₃ F H B-209. OCHF₂ 6-F F H B-210. OCHF₂ 6-CH₃ F H B-211. OCHF₂ 6-OCH₃ F H B-212. OCF₃ 3-F F H B-213. OCF₃ 3-CH₃ F H B-214. OCF₃ 3-OCH₃ F H B-215. OCF₃ 5-F F H B-216. OCF₃ 5-CH₃ F H B-217. OCF₃ 5-OCH₃ F H B-218. OCF₃ 6-F F H B-219. OCF₃ 6-CH₃ F H B-220. OCF₃ 6-OCH₃ F H B-221. H H Cl H B-222. F H Cl H B-223. CH₃ H Cl H B-224. OCH₃ H Cl H B-225. CN H Cl H B-226. CH₂F H Cl H B-227. CHF₂ H Cl H B-228. CF₃ H Cl H B-229. OCH₂F H Cl H B-230. OCHF₂ H Cl H B-231. OCF₃ H Cl H B-232. H 3-F Cl H B-233. H 3-CH₃ Cl H B-234. H 3-OCH₃ Cl H B-235. H 5-F Cl H B-236. H 5-CH₃ Cl H B-237. H 5-OCH₃ Cl H B-238. H 6-F Cl H B-239. H 6-CH₃ Cl H B-240. H 6-OCH₃ Cl H B-241. F 3-F Cl H B-242. F 3-CH₃ Cl H B-243. F 3-OCH₃ Cl H B-244. F 5-F Cl H B-245. F 5-CH₃ Cl H B-246. F 5-OCH₃ Cl H B-247. F 6-F Cl H B-248. F 6-CH₃ Cl H B-249. F 6-OCH₃ Cl H B-250. CH₃ 3-F Cl H B-251. CH₃ 3-CH₃ Cl H B-252. CH₃ 3-OCH₃ Cl H B-253. CH₃ 5-F Cl H B-254. CH₃ 5-CH₃ Cl H B-255. CH₃ 5-OCH₃ Cl H B-256. CH₃ 6-F Cl H B-257. CH₃ 6-CH₃ Cl H B-258. CH₃ 6-OCH₃ Cl H B-259. OCH₃ 3-F Cl H B-260. OCH₃ 3-CH₃ Cl H B-261. OCH₃ 3-OCH₃ Cl H B-262. OCH₃ 5-F Cl H B-263. OCH₃ 5-CH₃ Cl H B-264. OCH₃ 5-OCH₃ Cl H B-265. OCH₃ 6-F Cl H B-266. OCH₃ 6-CH₃ Cl H B-267. OCH₃ 6-OCH₃ Cl H B-268. CN 3-F Cl H B-269. CN 3-CH₃ Cl H B-270. CN 3-OCH₃ Cl H B-271. CN 5-F Cl H B-272. CN 5-CH₃ Cl H B-273. CN 5-OCH₃ Cl H B-274. CN 6-F Cl H B-275. CN 6-CH₃ Cl H B-276. CN 6-OCH₃ Cl H B-277. CH₂F 3-F Cl H B-278. CH₂F 3-CH₃ Cl H B-279. CH₂F 3-OCH₃ Cl H B-280. CH₂F 5-F Cl H B-281. CH₂F 5-CH₃ Cl H B-282. CH₂F 5-OCH₃ Cl H B-283. CH₂F 6-F Cl H B-284. CH₂F 6-CH₃ Cl H B-285. CH₂F 6-OCH₃ Cl H B-286. CHF₂ 3-F Cl H B-287. CHF₂ 3-CH₃ Cl H B-288. CHF₂ 3-OCH₃ Cl H B-289. CHF₂ 5-F Cl H B-290. CHF₂ 5-CH₃ Cl H B-291. CHF₂ 5-OCH₃ Cl H B-292. CHF₂ 6-F Cl H B-293. CHF₂ 6-CH₃ Cl H B-294. CHF₂ 6-OCH₃ Cl H B-295. CF₃ 3-F Cl H B-296. CF₃ 3-CH₃ Cl H B-297. CF₃ 3-OCH₃ Cl H B-298. CF₃ 5-F Cl H B-299. CF₃ 5-CH₃ Cl H B-300. CF₃ 5-OCH₃ Cl H B-301. CF₃ 6-F Cl H B-302. CF₃ 6-CH₃ Cl H B-303. CF₃ 6-OCH₃ Cl H B-304. OCH₂F 3-F Cl H B-305. OCH₂F 3-CH₃ Cl H B-306. OCH₂F 3-OCH₃ Cl H B-307. OCH₂F 5-F Cl H B-308. OCH₂F 5-CH₃ Cl H B-309. OCH₂F 5-OCH₃ Cl H B-310. OCH₂F 6-F Cl H B-311. OCH₂F 6-CH₃ Cl H B-312. OCH₂F 6-OCH₃ Cl H B-313. OCHF₂ 3-F Cl H B-314. OCHF₂ 3-CH₃ Cl H B-315. OCHF₂ 3-OCH₃ Cl H B-316. OCHF₂ 5-F Cl H B-317. OCHF₂ 5-CH₃ Cl H B-318. OCHF₂ 5-OCH₃ Cl H B-319. OCHF₂ 6-F Cl H B-320. OCHF₂ 6-CH₃ Cl H B-321. OCHF₂ 6-OCH₃ Cl H B-322. OCF₃ 3-F Cl H B-323. OCF₃ 3-CH₃ Cl H B-324. OCF₃ 3-OCH₃ Cl H B-325. OCF₃ 5-F Cl H B-326. OCF₃ 5-CH₃ Cl H B-327. OCF₃ 5-OCH₃ Cl H B-328. OCF₃ 6-F Cl H B-329. OCF₃ 6-CH₃ Cl H B-330. OCF₃ 6-OCH₃ Cl H B-331. H H CN F B-332. F H CN F B-333. CH₃ H CN F B-334. OCH₃ H CN F B-335. CN H CN F B-336. CH₂F H CN F B-337. CHF₂ H CN F B-338. CF₃ H CN F B-339. OCH₂F H CN F B-340. OCHF₂ H CN F B-341. OCF₃ H CN F B-342. H 3-F CN F B-343. H 3-CH₃ CN F B-344. H 3-OCH₃ CN F B-345. H 5-F CN F B-346. H 5-CH₃ CN F B-347. H 5-OCH₃ CN F B-348. H 6-F CN F B-349. H 6-CH₃ CN F B-350. H 6-OCH₃ CN F B-351. F 3-F CN F B-352. F 3-CH₃ CN F B-353. F 3-OCH₃ CN F B-354. F 5-F CN F B-355. F 5-CH₃ CN F B-356. F 5-OCH₃ CN F B-357. F 6-F CN F B-358. F 6-CH₃ CN F B-359. F 6-OCH₃ CN F B-360. CH₃ 3-F CN F B-361. CH₃ 3-CH₃ CN F B-362. CH₃ 3-OCH₃ CN F B-363. CH₃ 5-F CN F B-364. CH₃ 5-CH₃ CN F B-365. CH₃ 5-OCH₃ CN F B-366. CH₃ 6-F CN F B-367. CH₃ 6-CH₃ CN F B-368. CH₃ 6-OCH₃ CN F B-369. OCH₃ 3-F CN F B-370. OCH₃ 3-CH₃ CN F B-371. OCH₃ 3-OCH₃ CN F B-372. OCH₃ 5-F CN F B-373. OCH₃ 5-CH₃ CN F B-374. OCH₃ 5-OCH₃ CN F B-375. OCH₃ 6-F CN F B-376. OCH₃ 6-CH₃ CN F B-377. OCH₃ 6-OCH₃ CN F B-378. CN 3-F CN F B-379. CN 3-CH₃ CN F B-380. CN 3-OCH₃ CN F B-381. CN 5-F CN F B-382. CN 5-CH₃ CN F B-383. CN 5-OCH₃ CN F B-384. CN 6-F CN F B-385. CN 6-CH₃ CN F B-386. CN 6-OCH₃ CN F B-387. CH₂F 3-F CN F B-388. CH₂F 3-CH₃ CN F B-389. CH₂F 3-OCH₃ CN F B-390. CH₂F 5-F CN F B-391. CH₂F 5-CH₃ CN F B-392. CH₂F 5-OCH₃ CN F B-393. CH₂F 6-F CN F B-394. CH₂F 6-CH₃ CN F B-395. CH₂F 6-OCH₃ CN F B-396. CHF₂ 3-F CN F B-397. CHF₂ 3-CH₃ CN F B-398. CHF₂ 3-OCH₃ CN F B-399. CHF₂ 5-F CN F B-400. CHF₂ 5-CH₃ CN F B-401. CHF₂ 5-OCH₃ CN F B-402. CHF₂ 6-F CN F B-403. CHF₂ 6-CH₃ CN F B-404. CHF₂ 6-OCH₃ CN F B-405. CF₃ 3-F CN F B-406. CF₃ 3-CH₃ CN F B-407. CF₃ 3-OCH₃ CN F B-408. CF₃ 5-F CN F B-409. CF₃ 5-CH₃ CN F B-410. CF₃ 5-OCH₃ CN F B-411. CF₃ 6-F CN F B-412. CF₃ 6-CH₃ CN F B-413. CF₃ 6-OCH₃ CN F B-414. OCH₂F 3-F CN F B-415. OCH₂F 3-CH₃ CN F B-416. OCH₂F 3-OCH₃ CN F B-417. OCH₂F 5-F CN F B-418. OCH₂F 5-CH₃ CN F B-419. OCH₂F 5-OCH₃ CN F B-420. OCH₂F 6-F CN F B-421. OCH₂F 6-CH₃ CN F B-422. OCH₂F 6-OCH₃ CN F B-423. OCHF₂ 3-F CN F B-424. OCHF₂ 3-CH₃ CN F B-425. OCHF₂ 3-OCH₃ CN F B-426. OCHF₂ 5-F CN F B-427. OCHF₂ 5-CH₃ CN F B-428. OCHF₂ 5-OCH₃ CN F B-429. OCHF₂ 6-F CN F B-430. OCHF₂ 6-CH₃ CN F B-431. OCHF₂ 6-OCH₃ CN F B-432. OCF₃ 3-F CN F B-433. OCF₃ 3-CH₃ CN F B-434. OCF₃ 3-OCH₃ CN F B-435. OCF₃ 5-F CN F B-436. OCF₃ 5-CH₃ CN F B-437. OCF₃ 5-OCH₃ CN F B-438. OCF₃ 6-F CN F B-439. OCF₃ 6-CH₃ CN F B-440. OCF₃ 6-OCH₃ CN F B-441. H H F F B-442. F H F F B-443. CH₃ H F F B-444. OCH₃ H F F B-445. CN H F F B-446. CH₂F H F F B-447. CHF₂ H F F B-448. CF₃ H F F B-449. OCH₂F H F F B-450. OCHF₂ H F F B-451. OCF₃ H F F B-452. H 3-F F F B-453. H 3-CH₃ F F B-454. H 3-OCH₃ F F B-455. H 5-F F F B-456. H 5-CH₃ F F B-457. H 5-OCH₃ F F B-458. H 6-F F F B-459. H 6-CH₃ F F B-460. H 6-OCH₃ F F B-461. F 3-F F F B-462. F 3-CH₃ F F B-463. F 3-OCH₃ F F B-464. F 5-F F F B-465. F 5-CH₃ F F B-466. F 5-OCH₃ F F B-467. F 6-F F F B-468. F 6-CH₃ F F B-469. F 6-OCH₃ F F B-470. CH₃ 3-F F F B-471. CH₃ 3-CH₃ F F B-472. CH₃ 3-OCH₃ F F B-473. CH₃ 5-F F F B-474. CH₃ 5-CH₃ F F B-475. CH₃ 5-OCH₃ F F B-476. CH₃ 6-F F F B-477. CH₃ 6-CH₃ F F B-478. CH₃ 6-OCH₃ F F B-479. OCH₃ 3-F F F B-480. OCH₃ 3-CH₃ F F B-481. OCH₃ 3-OCH₃ F F B-482. OCH₃ 5-F F F B-483. OCH₃ 5-CH₃ F F B-484. OCH₃ 5-OCH₃ F F B-485. OCH₃ 6-F F F B-486. OCH₃ 6-CH₃ F F B-487. OCH₃ 6-OCH₃ F F B-488. CN 3-F F F B-489. CN 3-CH₃ F F B-490. CN 3-OCH₃ F F B-491. CN 5-F F F B-492. CN 5-CH₃ F F B-493. CN 5-OCH₃ F F B-494. CN 6-F F F B-495. CN 6-CH₃ F F B-496. CN 6-OCH₃ F F B-497. CH₂F 3-F F F B-498. CH₂F 3-CH₃ F F B-499. CH₂F 3-OCH₃ F F B-500. CH₂F 5-F F F B-501. CH₂F 5-CH₃ F F B-502. CH₂F 5-OCH₃ F F B-503. CH₂F 6-F F F B-504. CH₂F 6-CH₃ F F B-505. CH₂F 6-OCH₃ F F B-506. CHF₂ 3-F F F B-507. CHF₂ 3-CH₃ F F B-508. CHF₂ 3-OCH₃ F F B-509. CHF₂ 5-F F F B-510. CHF₂ 5-CH₃ F F B-511. CHF₂ 5-OCH₃ F F B-512. CHF₂ 6-F F F B-513. CHF₂ 6-CH₃ F F B-514. CHF₂ 6-OCH₃ F F B-515. CF₃ 3-F F F B-516. CF₃ 3-CH₃ F F B-517. CF₃ 3-OCH₃ F F B-518. CF₃ 5-F F F B-519. CF₃ 5-CH₃ F F B-520. CF₃ 5-OCH₃ F F B-521. CF₃ 6-F F F B-522. CF₃ 6-CH₃ F F B-523. CF₃ 6-OCH₃ F F B-524. OCH₂F 3-F F F B-525. OCH₂F 3-CH₃ F F B-526. OCH₂F 3-OCH₃ F F B-527. OCH₂F 5-F F F B-528. OCH₂F 5-CH₃ F F B-529. OCH₂F 5-OCH₃ F F B-530. OCH₂F 6-F F F B-531. OCH₂F 6-CH₃ F F B-532. OCH₂F 6-OCH₃ F F B-533. OCHF₂ 3-F F F B-534. OCHF₂ 3-CH₃ F F B-535. OCHF₂ 3-OCH₃ F F B-536. OCHF₂ 5-F F F B-537. OCHF₂ 5-CH₃ F F B-538. OCHF₂ 5-OCH₃ F F B-539. OCHF₂ 6-F F F B-540. OCHF₂ 6-CH₃ F F B-541. OCHF₂ 6-OCH₃ F F B-542. OCF₃ 3-F F F B-543. OCF₃ 3-CH₃ F F B-544. OCF₃ 3-OCH₃ F F B-545. OCF₃ 5-F F F B-546. OCF₃ 5-CH₃ F F B-547. OCF₃ 5-OCH₃ F F B-548. OCF₃ 6-F F F B-549. OCF₃ 6-CH₃ F F B-550. OCF₃ 6-OCH₃ F F B-551. H H Cl F B-552. F H Cl F B-553. CH₃ H Cl F B-554. OCH₃ H Cl F B-555. CN H Cl F B-556. CH₂F H Cl F B-557. CHF₂ H Cl F B-558. CF₃ H Cl F B-559. OCH₂F H Cl F B-560. OCHF₂ H Cl F B-561. OCF₃ H Cl F B-562. H 3-F Cl F B-563. H 3-CH₃ Cl F B-564. H 3-OCH₃ Cl F B-565. H 5-F Cl F B-566. H 5-CH₃ Cl F B-567. H 5-OCH₃ Cl F B-568. H 6-F Cl F B-569. H 6-CH₃ Cl F B-570. H 6-OCH₃ Cl F B-571. F 3-F Cl F B-572. F 3-CH₃ Cl F B-573. F 3-OCH₃ Cl F B-574. F 5-F Cl F B-575. F 5-CH₃ Cl F B-576. F 5-OCH₃ Cl F B-577. F 6-F Cl F B-578. F 6-CH₃ Cl F B-579. F 6-OCH₃ Cl F B-580. CH₃ 3-F Cl F B-581. CH₃ 3-CH₃ Cl F B-582. CH₃ 3-OCH₃ Cl F B-583. CH₃ 5-F Cl F B-584. CH₃ 5-CH₃ Cl F B-585. CH₃ 5-OCH₃ Cl F B-586. CH₃ 6-F Cl F B-587. CH₃ 6-CH₃ Cl F B-588. CH₃ 6-OCH₃ Cl F B-589. OCH₃ 3-F Cl F B-590. OCH₃ 3-CH₃ Cl F B-591. OCH₃ 3-OCH₃ Cl F B-592. OCH₃ 5-F Cl F B-593. OCH₃ 5-CH₃ Cl F B-594. OCH₃ 5-OCH₃ Cl F B-595. OCH₃ 6-F Cl F B-596. OCH₃ 6-CH₃ Cl F B-597. OCH₃ 6-OCH₃ Cl F B-598. CN 3-F Cl F B-599. CN 3-CH₃ Cl F B-600. CN 3-OCH₃ Cl F B-601. CN 5-F Cl F B-602. CN 5-CH₃ Cl F B-603. CN 5-OCH₃ Cl F B-604. CN 6-F Cl F B-605. CN 6-CH₃ Cl F B-606. CN 6-OCH₃ Cl F B-607. CH₂F 3-F Cl F B-608. CH₂F 3-CH₃ Cl F B-609. CH₂F 3-OCH₃ Cl F B-610. CH₂F 5-F Cl F B-611. CH₂F 5-CH₃ Cl F B-612. CH₂F 5-OCH₃ Cl F B-613. CH₂F 6-F Cl F B-614. CH₂F 6-CH₃ Cl F B-615. CH₂F 6-OCH₃ Cl F B-616. CHF₂ 3-F Cl F B-617. CHF₂ 3-CH₃ Cl F B-618. CHF₂ 3-OCH₃ Cl F B-619. CHF₂ 5-F Cl F B-620. CHF₂ 5-CH₃ Cl F B-621. CHF₂ 5-OCH₃ Cl F B-622. CHF₂ 6-F Cl F B-623. CHF₂ 6-CH₃ Cl F B-624. CHF₂ 6-OCH₃ Cl F B-625. CF₃ 3-F Cl F B-626. CF₃ 3-CH₃ Cl F B-627. CF₃ 3-OCH₃ Cl F B-628. CF₃ 5-F Cl F B-629. CF₃ 5-CH₃ Cl F B-630. CF₃ 5-OCH₃ Cl F B-631. CF₃ 6-F Cl F B-632. CF₃ 6-CH₃ Cl F B-633. CF₃ 6-OCH₃ Cl F B-634. OCH₂F 3-F Cl F B-635. OCH₂F 3-CH₃ Cl F B-636. OCH₂F 3-OCH₃ Cl F B-637. OCH₂F 5-F Cl F B-638. OCH₂F 5-CH₃ Cl F B-639. OCH₂F 5-OCH₃ Cl F B-640. OCH₂F 6-F Cl F B-641. OCH₂F 6-CH₃ Cl F B-642. OCH₂F 6-OCH₃ Cl F B-643. OCHF₂ 3-F Cl F B-644. OCHF₂ 3-CH₃ Cl F B-645. OCHF₂ 3-OCH₃ Cl F B-646. OCHF₂ 5-F Cl F B-647. OCHF₂ 5-CH₃ Cl F B-648. OCHF₂ 5-OCH₃ Cl F B-649. OCHF₂ 6-F Cl F B-650. OCHF₂ 6-CH₃ Cl F B-651. OCHF₂ 6-OCH₃ Cl F B-652. OCF₃ 3-F Cl F B-653. OCF₃ 3-CH₃ Cl F B-654. OCF₃ 3-OCH₃ Cl F B-655. OCF₃ 5-F Cl F B-656. OCF₃ 5-CH₃ Cl F B-657. OCF₃ 5-OCH₃ Cl F B-658. OCF₃ 6-F Cl F B-659. OCF₃ 6-CH₃ Cl F B-660. OCF₃ 6-OCH₃ Cl F

The positions (e.g. 3-/5-/6-) of R³ are relative to the 2- and 4-positions of radicals R¹ and R² and to the 1-position of the attachment point of the ring to the SO₂ group.

The preferred compounds among the compounds I.1 to I.72 mentioned above are those of the formulae I.1 to I.6 and I.37 to I.42, and especially compounds of the formulae I.1 to I.6. Particularly preferred are compounds of the formulae I.1 to I.3.

In a specific embodiment, the compounds I are selected from the compounds specified in the examples, either as a free base or in form of a pharmaceutically acceptable salt, an N-oxide or a stereoisomer or the racemate or any mixture of the steroisomers thereof.

The compounds I of the invention have a center of chirality in position 3 of the 2-oxindole ring. The compounds of the invention may therefore be in the form of a 1:1 mixture of enantiomers (racemate) or of a nonracemic mixture of enantiomers in which one of the two enantiomers, either the enantiomer which rotates the plane of vibration of linearly polarized light to the left (i.e. minus rotation) (hereinafter (−) enantiomer) or the enantiomer which rotates the plane of vibration of linearly polarized light to the right (i.e. plus rotation) (hereinafter (+) enantiomer), is enriched, or of substantially enantiopure compounds, that is to say of substantially enantiopure (−) enantiomer or (+) enantiomer. Since the compounds of the invention have a single center of asymmetry and no axis/plane of chirality, a nonracemic mixture can also be defined as a mixture of enantiomers in which either the R or the S enantiomer predominates. Substantially enantiopure compounds can accordingly also be defined as substantially enantiopure R enantiomer or substantially enantiopure S enantiomer.

“Substantially enantiopure compounds” means in the context of the present invention those compounds having an enantiomeric excess (ee; % ee=(R−S)/(R+S)×100 or (S−R)/(S+R)×100) of at least 80% ee, preferably at least 85% ee, more preferably at least 90% ee, even more preferably at least 95% ee and in particular at least 98% ee.

In one embodiment of the invention, the compounds of the invention are in the form of substantially enantiopure compounds. Particularly preferred compounds have an enantiomeric excess of at least 85% ee, more preferably of at least 90% ee, even more preferably of at least 95% ee and in particular of at least 98% ee.

The invention thus relates both to the pure enantiomers and to mixtures thereof, e.g. mixtures in which one enantiomer is present in enriched form, but also to the racemates. The invention also relates to the pharmaceutically acceptable salts of the pure enantiomers of compounds I, and the mixtures of enantiomers in the form of the pharmaceutically acceptable salts of compounds I.

Preferred embodiments of the invention are compounds of the formula I as detailed above which are characterized in that they are in optically active form, and the enantiomer of the relevant compound of the formula I is the S-enantiomner, in the form of a free base, or a pharmaceutically acceptable salt thereof.

Particularly preference is given to compounds of the general formula I and their pharmaceutically acceptable salts as detailed above in which the corresponding S-enantiomer is present in an optical purity (enantiomeric excess, ee) of more than 50% ee, particularly preferably of at least 80% ee, more preferably of at least 90% ee and even more preferably of at least 95% ee and in particular of at least 98% ee.

Likewise preferred embodiments of the invention are compounds of the general formula I as detailed above which are characterized in that they are in optically inactive form, i.e. in the form of the racemate, or in the form of a pharmaceutically acceptable salt of the racemate.

Examples of synthetic routes for preparing the oxindole derivatives of the invention are described below.

The compounds of the invention can be prepared by using methods described in WO 2005/030755, WO 2006/005609 and the other references mentioned in the outset for synthesizing analogous compounds, and the preparation is outlined by way of example in synthesis scheme 1. The variables in these synthetic schemes have the same meanings as in formula I.

The 3-hydroxy-1,3-dihydroindol-2-ones IV can be obtained by addition of metallated heterocycles III onto the 3-keto group of the isatins II. The metallated heterocycles, such as, for example, the corresponding Grignard (Mg) or organyllithium compound, can be obtained in any conventional way from halogen or hydrocarbon compounds. Examples of methods are present in Houben-Weyl, Methoden der Organischen Chemie, vol. 13, 1-2, chapter on Mg and Li compounds. The isatins II are either commercially available or were prepared in analogy to methods described in the literature (Advances in Heterocyclic Chemistry, A. R. Katritzky and A. J. Boulton, Academic Press, New York, 1975, 18, 2-58; J. Brazil. Chem. Soc. 12, 273-324, 2001).

The 3-hydroxyoxindoles IV can be converted into the compounds V which have a leaving group LG′ in position 3, where the leaving group LG′ is a conventional leaving group such as, for example, chlorine or bromide. The intermediate V with for example LG′=chlorine can be prepared by treating the alcohol IV with thionyl chloride in the presence of a base such as, for example, pyridine, in a suitable solvent such as, for example, dichloromethane.

The compounds V can subsequently be reacted with amines, such as, for example, ammonia, in a substitution reaction to give the amines VI. The compounds VI can subsequently be converted by treatment with sulfonyl chlorides VII after deprotonation with a strong base such as, for example, potassium tert-butoxide or sodium hydride in DMF into the sulfonylated product VIII. The sulfonyl chlorides VII employed can either be purchased or be prepared by known processes (for example J. Med. Chem. 40, 1149 (1997)). The compounds VIII are then reacted with phenyl chloroformate in the presence of a base such as, for example, pyridine to give the corresponding phenyl carbamate IX.

The compounds of the invention of the general formula I which have a urea group in position 3 can be prepared as described in WO 2005/030755 and WO 2006/005609, and shown in synthesis scheme 1, by two different sequences: In the first variant, compound IX is first reacted with amine X, where appropriate at elevated temperature and with the addition of auxiliary bases such as, for example, triethylamine or diisopropylethylamine. PG is a protective group, typically Boc. Subsequent deprotection (for Boc typically treatment with trifluoroacetic acid in dichloromethane) yields compound XII, which is then reacted with the oxetan-3-one XIII to give compound I with X³ being a bond. The latter reaction is carried out in the presence of a suitable reduction agent, e.g. boron-based reduction agent, typically a boronic ester, such as sodium triacetoxyhydroborate, or cyanoborhydride. For obtaining compounds wherein X³ is CH₂, oxetane-3-carbaldehyde optionally carrying c substituents R¹⁰ is used instead of oxetanone XIII. For obtaining compounds wherein X³ is CO, oxetane-3-carbonylchloride optionally carrying c substituents R¹⁰ is used instead of oxetanone XIII.

In the second variant, compound IX is reacted with the amine XIV. The reaction is generally carried out in the presence of a base, such as triethylamine or diisopropylethylamine.

The amines X can be either purchased or prepared by methods known from the literature. Compounds XIV wherein X³ is a bond can be prepared by reacting a compound X with oxetan-3-one carrying c substituents R¹⁰ in the presence of a reduction agent such as sodium triacetoxyhydroborate or cyanoborhydride. For obtaining compounds XIV wherein X³ is CH₂, oxetane-3-carbaldehyde carrying c substituents R¹⁰ is used instead of the oxetan-3-one XIII. Analogously, for obtaining compounds XIV wherein X³ is C₂-C₄-alkylene, oxetane carrying in the 3-position a C₂-C₄-keto or aldehyde group (e.g. a group CH₂CHO, CH₂CH₂CHO, (CH₂)₃CHO, CH₂COCH₃, CH₂CH₂COCH₃ etc.) and carrying c substituents R¹⁰ is used instead of the oxetan-3-one XIII. Such oxetanes are either commercially available or can be prepared by routine methods. For obtaining compounds wherein X³ is CO, oxetane-3-carbonylchloride carrying c substituents R¹⁰ is used instead of the oxetan-3-one XIII.

If not indicated otherwise, the above-described reactions are generally carried out in a solvent at temperatures between room temperature and the boiling temperature of the solvent employed. Alternatively, the activation energy which is required for the reaction can be introduced into the reaction mixture using microwaves, something which has proved to be of value, in particular, in the case of the reactions catalyzed by transition metals (with regard to reactions using microwaves, see Tetrahedron 2001, 57, p. 9199 ff. p. 9225 ff. and also, in a general manner, “Microwaves in Organic Synthesis”, André Loupy (Ed.), Wiley-VCH 2002.

The acid addition salts of compounds I are prepared in a customary manner by mixing the free base with a corresponding acid, where appropriate in solution in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl tert-butyl ether or diisopropyl ether, a ketone, such as acetone or methyl ethyl ketone, or an ester, such as ethyl acetate.

Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that may not be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the preparation methods are within routine techniques.

Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the invention may be accomplished by methods analogous to those described in the synthetic scheme described hereinabove and in specific examples.

Starting materials, if not commercially available, may be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described schemes or the procedures described in the synthetic examples section.

When an optically active form of a compound of the invention is required, it may be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.

The present invention moreover relates to compounds of formula I as defined above, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope (e.g., hydrogen by deuterium, ¹²C by ¹³C, ¹⁴N by ¹⁵N, ¹⁶O by ¹⁸O) and preferably wherein at least one hydrogen atom has been replaced by a deuterium atom.

Of course, the compounds according to the invention contain more of the respective isotope than this naturally occurs and thus is anyway present in the compounds I.

Stable isotopes (e.g., deuterium, ¹³C, ¹⁵N, ¹⁸O) are nonradioactive isotopes which contain one additional neutron than the normally abundant isotope of the respective atom. Deuterated compounds have been used in pharmaceutical research to investigate the in vivo metabolic fate of the compounds by evaluation of the mechanism of action and metabolic pathway of the non deuterated parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic studies are important in the design of safe, effective therapeutic drugs, either because the in vivo active compound administered to the patient or because the metabolites produced from the parent compound prove to be toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut., 36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol., 77, 79-88 (1999).

Incorporation of a heavy atom, particularly substitution of deuterium for hydrogen, can give rise to an isotope effect that could alter the pharmacokinetics of the drug.

Stable isotope labeling of a drug can alter its physico-chemical properties such as pKa and lipid solubility. These changes may influence the fate of the drug at different steps along its passage through the body. Absorption, distribution, metabolism or excretion can be changed. Absorption and distribution are processes that depend primarily on the molecular size and the lipophilicity of the substance. These effects and alterations can affect the pharmacodynamic response of the drug molecule if the isotopic substitution affects a region involved in a ligand-receptor interaction.

Drug metabolism can give rise to large isotopic effect if the breaking of a chemical bond to a deuterium atom is the rate limiting step in the process. While some of the physical properties of a stable isotope-labeled molecule are different from those of the unlabeled one, the chemical and biological properties are the same, with one important exception: because of the increased mass of the heavy isotope, any bond involving the heavy isotope and another atom will be stronger than the same bond between the light isotope and that atom. In any reaction in which the breaking of this bond is the rate limiting step, the reaction will proceed slower for the molecule with the heavy isotope due to “kinetic isotope effect”. A reaction involving breaking a C-D bond can be up to 700 percent slower than a similar reaction involving breaking a C—H bond. If the C-D bond is not involved in any of the steps leading to the metabolite, there may not be any effect to alter the behavior of the drug. If a deuterium is placed at a site involved in the metabolism of a drug, an isotope effect will be observed only if breaking of the C-D bond is the rate limiting step. There is evidence to suggest that whenever cleavage of an aliphatic C—H bond occurs, usually by oxidation catalyzed by a mixed-function oxidase, replacement of the hydrogen by deuterium will lead to observable isotope effect. It is also important to understand that the incorporation of deuterium at the site of metabolism slows its rate to the point where another metabolite produced by attack at a carbon atom not substituted by deuterium becomes the major pathway a process called “metabolic switching”.

Deuterium tracers, such as deuterium-labeled drugs and doses, in some cases re-peatedly, of thousands of milligrams of deuterated water, are also used in healthy humans of all ages, including neonates and pregnant women, without reported incident (e.g. Pons G and Rey E, Pediatrics 1999 104: 633; Coward W A et al., Lancet 1979 7: 13; Schwarcz H P, Control. Clin. Trials 1984 5(4 Suppl): 573; Rodewald L E et al., J. Pediatr. 1989 114: 885; Butte N F et al. Br. J. Nutr. 1991 65: 3; MacLennan A H et al. Am. J. Obstet Gynecol. 1981 139: 948). Thus, it is clear that any deuterium released, for instance, during the metabolism of compounds of this invention poses no health risk.

The weight percentage of hydrogen in a mammal (approximately 9%) and natural abundance of deuterium (approximately 0.015%) indicates that a 70 kg human normally contains nearly a gram of deuterium. Furthermore, replacement of up to about 15% of normal hydrogen with deuterium has been effected and maintained for a period of days to weeks in mammals, including rodents and dogs, with minimal observed adverse effects (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson J F, Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al., Am. J. Physiol. 1961 201: 357). Higher deuterium concentrations, usually in excess of 20%, can be toxic in animals. However, acute replacement of as high as 15%-23% of the hydrogen in humans' fluids with deuterium was found not to cause toxicity (Blagojevic N et al. in “Dosimetry & Treatment Planning for Neutron Capture Therapy”, Zamenhof R, Solares G and Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp. 125-134; Diabetes Metab. 23: 251 (1997)).

Increasing the amount of deuterium present in a compound above its natural abundance is called enrichment or deuterium-enrichment. Examples of the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol %.

The hydrogens present on a particular organic compound have different capacities for exchange with deuterium. Certain hydrogen atoms are easily exchangeable under physiological conditions and, if replaced by deuterium atoms, it is expected that they will readily exchange for protons after administration to a patient. Certain hydrogen atoms may be exchanged for deuterium atoms by the action of a deuteric acid such as D₂SO₄/D₂O. Alternatively, deuterium atoms may be incorporated in various combinations during the synthesis of compounds of the invention. Certain hydrogen atoms are not easily exchangeable for deuterium atoms. However, deuterium atoms at the remaining positions may be incorporated by the use of deuterated starting materials or intermediates during the construction of compounds of the invention.

Deuterated and deuterium-enriched compounds of the invention can be prepared by using known methods described in the literature. Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure. Relevant procedures and intermediates are disclosed, for instance in Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996); Brickner, S J et al., J Med Chem, 39(3), 673 (1996); Mallesham, B et al., Org Lett, 5(7), 963 (2003); PCT publications WO1997010223, WO2005099353, WO1995007271, WO2006008754; U.S. Pat. Nos. 7,538,189; 7,534,814; 7,531,685; 7,528,131; 7,521,421; 7,514,068; 7,511,013; and US Patent Application Publication Nos. 20090137457; 20090131485; 20090131363; 20090118238; 20090111840; 20090105338; 20090105307; 20090105147; 20090093422; 20090088416; 20090082471, the methods are hereby incorporated by reference.

A further aspect of the present invention relates to a pharmaceutical composition comprising at least one compound of the general formula I and/or an N-oxide, a stereoisomer or a pharmaceutically acceptable salt thereof as detailed above, and a pharmaceutically acceptable carrier; or comprising at least one compound I wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope, preferably wherein at least one hydrogen atom has been replaced by a deuterium atom, in combination with at least one pharmaceutically acceptable carrier and/or auxiliary substance. Suitable carriers depend inter alia on the dosage form of the composition and are known in principle to the skilled worker. Some suitable carriers are described hereinafter.

The present invention furthermore relates to a compound I as defined above or an N-oxide, a stereoisomer or a pharmaceutically acceptable salt thereof for use as a medicament. The present invention also relates to a compound I as defined above or an N-oxide, a stereoisomer or a pharmaceutically acceptable salt thereof for the treatment of vasopressin-related diseases, especially of disorders which respond to the modulation of the vasopressin receptor and in particular of the V1b receptor.

A further aspect of the present invention relates to the use of compounds of the formula I and/or of an N-oxide, a stereoisomer or of pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment and/or prophylaxis of vasopressin-related diseases, especially of disorders which respond to the modulation of the vasopressin receptor and in particular of the V1b receptor.

Vasopressin-related diseases are those in which the progress of the disease is at least partly dependent on vasopressin, i.e. diseases which show an elevated vasopressin level which may contribute directly or indirectly to the pathological condition. In other words, vasopressin-related diseases are those which can be influenced by modulating the vasopressin receptor, for example by administration of a vasopressin receptor ligand (agonist, antagonist, partial antagonist/agonist, inverse agonist etc.).

Affective disorders have been related to excessive vasopressin function. Therefore, treatment with compounds targeting the vasopressin system, such as vasopressin antagonists are likely to benefit patients suffering from affective disorders (see for example Surget A., Belzung C., Involvement of vasopressin in affective disorders, Eur. J. Pharm. 2008, 583, 340-349). Affective disorders (mood disorders) include depressive disorders, anxiety disorders, obsessive-compulsive and related disorders, trauma and stressor-related disorders as well as bipolar and related disorders. V1b antagonist have been shown to have anti-drug abuse effects and reduce drug withdrawal effect (see e.g. Zhou Y., Leri F., Cummins E., Hoeschele M., Kreek M. J., Involvement of arginine vasopressin and V1b receptor in heroin withdrawal and heroin seeking precipitated by stress and by heroin. Neuropsychopharmacology, 2008, 33, 226-236). Therefore, compound targeting the vasopressin system, such as vasopressin antagonists are thought to be effective for treatment of Substance-Related and Addictive Disorders. V1b receptors play a role in a range of emotional responses such as aggression. Attenuating V1b receptor function genetically or with antagonist reduces aggressive behavior (Blanchard R. J., Griebel G., Farrokhi C., Markham C., Yang M., Blanchard D. C., AVP V1b selective antagonist SSR149415 blocks aggressive behaviors in hamsters. Pharmacol. Biochem. Behav. 2005, 80, 189-194; Wersinger S. R., Ginns E. I., O'Carroll A. M., Lolait S. J., Young W. S., III, Vasopressin V1b receptor knockout reduces aggressive behavior in male mice. Mol. Psychiatry, 2002, 7, 975-984). Therefore, attenuating V1b antagonists functioning is likely to reduce aggression and agitation in disorders such as Alzheimer's disease and schizophrenia.

High cortisol levels have been correlated to reduced cognitive performance in elderly and AD (Alzheimer's disease) patients, and such correlations are more pronounced in subjects carrying the APOs4 allele, which is a risk factor for AD (see for example Lee B. K., Glass T. A., Wand G. S., McAtee M. J., Bandeen-Roche K., Bolla K. I., Schwartz B. S., Apolipoprotein e genotype, cortisol, and cognitive function in community-dwelling older adults. Am. J. Psychiatry 2008, 165, 1456-1464). Furthermore, increased plasma cortisol has been associated with more rapid disease progression in AD patients. Animal studies show an interaction between glucocorticoids and AD pathology, including amyloid precursor protein and tau accumulation (see for example Budas G., Coughlan C. M., Seckl J. R., Breen K. C., The effect of corticosteroids on amyloid beta precursor protein/amyloid precursor-like protein expression and processing in vivo. Neurosci. Lett., 1999, 276, 61-64). Cognitive performance can be impaired by stress or exposure to high doses of corticosterone in laboratory animals (for review see Roozendaal B., Systems mediating acute glucocorticoid effects on memory consolidation and retrieval. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2003, 27, 1213-1223). Therefore, lowering cortisol by treatment with V1b antagonist may enhance cognition or prevent/slow down the pathology or cognitive decline Alzheimer's Disease patients and in patients with other cognitive impairment such as schizophrenia and depression.

In a preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of an N-oxide, a stereoisomer or of pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from diabetes, insulin resistance, nocturnal enuresis, incontinence and diseases in which impairments of blood clotting occur, and/or for delaying micturition. The term “diabetes” means all types of diabetes, especially diabetes mellitus (including type I and especially type II), diabetes renalis and in particular diabetes insipidus. The types of diabetes are preferably diabetes mellitus of type II (with insulin resistance) or diabetes insipidus.

In a further preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of an N-oxide, a stereoisomer or of pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diseases selected from hypertension, pulmonary hypertension, heart failure, myocardial infarction, coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty), ischemias of the heart, impairments of the renal system, edemas, renal vasospasm, necrosis of the renal cortex, hyponatremia, hypokalemia, Schwartz-Bartter syndrome, impairments of the gastrointestinal tract, gastritic vasospasm, hepatocirrhosis, gastric and intestinal ulcers, emesis, emesis occurring during chemotherapy, and travel sickness.

The compounds of the invention of the formula I or their N-oxides, stereoisomers or pharmaceutically acceptable salts or the pharmaceutical composition of the invention can also be used for the treatment of various vasopressin-related complaints which have central nervous causes or alterations in the HPA axis (hypothalamic pituitary adrenal axis), for example for affective disorders such as depressive disorders, anxiety disorders, obsessive-compulsive and related disorders, trauma and stressor-related disorders, and bipolar and related disorders. Depressive disorders include for example dysthymic disorders, major depression, seasonal depression, treatment-resistant depression disorders, disruptive mood dysregulation disorder, premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, bipolar disorders, or childhood onset mood disorders. Anxiety disorders include for example phobias, specific phobias, general anxiety disorders, panic disorders, drug withdrawal-induced anxiety disorders, separation anxiety disorder, selective mutism, social anxiety disorder, agoraphobia, substance/medication-induced anxiety disorder and anxiety disorder due to another medical condition. Obsessive-compulsive and related disorders include for example obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania, excoriation disorder, substance/medication-induced obsessive-compulsive and related disorder and other specified obsessive-compulsive and related disorders. Trauma and stressor-related disorders include for example reactive attachment disorder, disinhibited social engagement disorder, post traumatic stress disorder, acute stress disorder, adjustment disorder and other specified trauma- and stressor-related disorders. Bipolar and related disorders include for example bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance/medication-induced bipolar and related disorder, bipolar and related disorder due to another medical condition and unspecified bipolar and related disorder.

Vasopressin-related complaints which have central nervous causes or alterations in the HPA axis are further cognitive disorders such as Alzheimer's disease, MCI (Mild Cognitive Impairment) and CIAS (Cognitive Impairment Associated with Schizophrenia).

The compounds of the invention of the formula I and their N-oxides, a stereoisomers or pharmaceutically acceptable salts or the pharmaceutical composition of the invention can likewise be employed for the treatment of anxiety disorders and stress-dependent anxiety disorders, such as, for example, generalized anxiety disorders, phobias, specific phobias, post-traumatic anxiety disorders, panic anxiety disorders, obsessive-compulsive anxiety disorders, acute stress-dependent anxiety disorders, drug withdrawal-induced anxiety disorders, separation anxiety disorder, selective mutism, social anxiety disorder, agoraphobia, substance/medication-induced anxiety disorder and anxiety disorder due to another medical condition and social phobia. The compounds of the invention of the formula I and their N-oxides, a stereoisomers or pharmaceutically acceptable salts or the pharmaceutical composition of the invention can likewise be employed for the treatment of obsessive-compulsive and related disorders, including, for example, obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania, excoriation disorder, substance/medication-induced obsessive-compulsive and related disorder and other specified obsessive-compulsive and related disorders. The compounds of the invention of the formula I and their N-oxides, a stereoisomers or pharmaceutically acceptable salts or the pharmaceutical composition of the invention can likewise be employed for the treatment of trauma and stressor-related disorders, including, for example, reactive attachment disorder, disinhibited social engagement disorder, post traumatic stress disorder, acute stress disorder, adjustment disorder and other specified trauma- and stressor-related disorders.

The compounds of the invention of the formula I and their N-oxides, stereoisomers or pharmaceutically acceptable salts or the pharmaceutical composition of the invention can likewise be employed for the treatment and/or prophylaxis of social impairment, such as autism or social impairment related with schizophrenia.

The compounds of the invention of the formula I and their N-oxides, stereoisomers or pharmaceutically acceptable salts or the pharmaceutical composition of the invention can likewise be employed for the treatment and/or prophylaxis of increased aggression in conditions such as Alzheimer's disease and schizophrenia.

The compounds of the invention can furthermore also be employed for the treatment of memory impairments, Alzheimer's disease, psychoses, psychotic disorders, sleep disorders and/or Cushing's syndrome, and all stress-dependent diseases.

Accordingly, a further preferred embodiment of the present invention relates to the use of compounds of the invention of the formula I or of an N-oxide, a stereoisomer or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of affective disorders.

In a further preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of an N-oxide, a stereoisomer or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of anxiety disorders and/or stress-dependent anxiety disorders.

In a further preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of an N-oxide, a stereoisomer or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of memory impairments and/or Alzheimer's disease.

In a further preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of an N-oxide, a stereoisomer or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of psychoses and/or psychotic disorders.

In a further preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of an N-oxide, a stereoisomer or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of Cushing's syndrome or other stress-dependent diseases.

In a further preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of an N-oxide, a stereoisomer or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of sleep disorders.

In a further preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of an N-oxide, a stereoisomer or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of depressive disorders. In the case of depressive disorders, specific mention is to be made of childhood onset mood disorders, i.e. depressive moods having their onset in childhood, but also of major depression, seasonal depression, bipolar and related disorders, dysthymic disorders, disruptive mood dysregulation disorder, premenstrual dysphoric disorder, substance/medication-induced depressive disorder, and depressive disorder due to another medical condition, and especially of major depression and seasonal depression as well as of the depressive phases of bipolar disorders. Bipolar and related disorders include for example bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance/medication-induced bipolar and related disorder, bipolar and related disorder due to another medical condition and unspecified bipolar and related disorder. The invention also relates to compounds of the formula I or N-oxides, stereoisomers or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of treatment-resistant depression disorders and for the use in an add-on therapy of depressive disorders.

In a further preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of an N-oxide, a stereoisomer or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of vasomotor symptoms and/or thermoregulatory dysfunctions such as, for example, the hot flush symptom.

In a further preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of an N-oxide, a stereoisomer or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment and/or prophylaxis of drug or pharmaceutical dependencies and/or dependencies mediated by other factors, for the treatment of drug-use disorders, for the treatment and/or prophylaxis of stress caused by withdrawal of one or more factors mediating the dependence and/or for the treatment and/or prophylaxis of stress-induced relapses into drug or pharmaceutical dependencies and/or dependencies mediated by other factors. To be more precise, the present invention relates to the use of compounds of the invention of the formula I or of an N-oxide, a stereoisomer or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment and/or prophylaxis of substance-related and addictive disorders such as substance use disorder, substance-induced disorder, alcohol use disorder, alcohol intoxication, alcohol withdrawal, unspecified alcohol-related disorder, caffeine intoxication, caffeine withdrawal, unspecified caffeine disorder, cannabis use disorder, cannabis withdrawal, unspecified cannabis-related disorder, phencyclidine use disorder, other hallucinogen use disorders, phencyclidine intoxication, other hallucinogen disorders, hallucinogen persisting perception disorder, unspecified phencyclidine disorder, inhalant use disorder, inhalant intoxication, opioid use disorder, opioid withdrawal, sedative, hypnotic or anxiolytic use disorder, sedative, hypnotic or anxiolytic withdrawal, stimulant use disorder, stimulant intoxication, stimulant withdrawal, tobacco use disorder, tobacco withdrawal, unspecified tobacco-related disorder, other (or unknown) substance use disorders, other (or unknown) substance intoxication, other (or unknown) substance withdrawal, other (or unknown) substance related disorder and gambling disorder.

In a further preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of an N-oxide, a stereoisomer or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment and/or prophylaxis of schizophrenia and/or psychosis.

In a further preferred embodiment, the present invention relates to the use of compounds of the invention of the formula I or of an N-oxide, a stereoisomer or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment and/or prophylaxis of pain, e.g. acute or chronic pain, preferably chronic pain, especially neuropathic pain. Chronic pain may be a complex regional pain syndrome, pain arising from peripheral neuropathies, post-operative pain, chronic fatigue syndrome pain, tension-type headache, pain arising from mechanical nerve injury and severe pain associated with diseases such as cancer, metabolic disease, neurotropic viral disease, neurotoxicity, inflammation, multiple sclerosis or any pain arising as a consequence of or associated with stress or depressive illness.

A further aspect of the invention relates to a compound I or pharmaceutically acceptable salts thereof for use as a medicament, and to a compound I or an N-oxide, a stereoisomer or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment and/or prophylaxis of the above-defined diseases.

A further aspect of the invention relates to a method for the treatment and/or prophylaxis of vasopressin-related diseases, in which an effective amount of at least one compound of the invention of the formula I or of an N-oxide, a stereoisomer or of at least one pharmaceutically acceptable salt thereof or of a pharmaceutical composition of the invention is administered to a patient.

Concerning the definition of vasopressin-related diseases, reference is made to the above statements.

In a preferred embodiment of the invention, the method of the invention serves for the treatment and/or prophylaxis of disorders selected from diabetes, insulin resistance, nocturnal enuresis, incontinence and diseases in which impairments of blood clotting occur, and/or for delaying micturition. Concerning the definition of diabetes, reference is made to the above statements.

In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of disorders selected from hypertension, pulmonary hypertension, heart failure, myocardial infarction, coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty), ischemias of the heart, impairments of the renal system, edemas, renal vasospasm, necrosis of the renal cortex, hyponatremia, hypokalemia, Schwartz-Bartter syndrome, impairments of the gastrointestinal tract, gastritic vasospasm, hepatocirrhosis, gastric and intestinal ulcers, emesis, emesis occurring during chemotherapy, and travel sickness.

In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of affective disorders.

In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of anxiety disorders and/or stress-dependent anxiety disorders.

In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of memory impairments and/or Alzheimer's disease.

In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of psychoses and/or psychotic disorders.

In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of Cushing's syndrome.

In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of sleep disorders in a patient.

In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of depressive disorders. In the case of depressive disorders, specific mention is to be made of major depression, seasonal depression, bipolar and related disorders, dysthymic disorders, childhood onset mood disorders, i.e. depressive moods having their onset in childhood, disruptive mood dysregulation disorder, premenstrual dysphoric disorder, substance/medication-induced depressive disorder, and depressive disorder due to another medical condition, and especially of major depression and seasonal depression as well as of the depressive phases of bipolar disorders. Bipolar and related disorders include for example bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance/medication-induced bipolar and related disorder, bipolar and related disorder due to another medical condition and unspecified bipolar and related disorder. The method of the invention also serves for the treatment of treatment-resistant depression disorders and as an add-on therapy of depressive disorders.

In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of vasomotor symptoms and/or thermoregulatory dysfunctions, such as, for example, the hot flush symptom.

In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of drug or pharmaceutical dependencies and/or dependencies mediated by other factors, for the treatment of drug-use disorders, for the treatment and/or prophylaxis of stress caused by withdrawal of one or more factors mediating the dependence, and/or for the treatment and/or prophylaxis of stress-induced relapses into drug or pharmaceutical dependencies and/or dependencies mediated by other factors. To be more precise, the method of the invention serves for the treatment and/or prophylaxis of substance-related and addictive disorders such as substance use disorder, substance-induced disorder, alcohol use disorder, alcohol intoxication, alcohol withdrawal, unspecified alcohol-related disorder, caffeine intoxication, caffeine withdrawal, unspecified caffeine disorder, cannabis use disorder, cannabis withdrawal, unspecified cannabis-related disorder, phencyclidine use disorder, other hallucinogen use disorders, phencyclidine intoxication, other hallucinogen disorders, hallucinogen persisting perception disorder, unspecified phencyclidine disorder, inhalant use disorder, inhalant intoxication, opioid use disorder, opioid withdrawal, sedative, hypnotic or anxiolytic use disorder, sedative, hypnotic or anxiolytic withdrawal, stimulant use disorder, stimulant intoxication, stimulant withdrawal, tobacco use disorder, tobacco withdrawal, unspecified tobacco-related disorder, other (or unknown) substance use disorders, other (or unknown) substance intoxication, other (or unknown) substance withdrawal, other (or unknown) substance related disorder and gambling disorder.

In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of schizophrenia and/or psychosis.

In a further preferred embodiment, the method of the invention serves for the treatment and/or prophylaxis of pain, e.g. acute or chronic pain, preferably chronic pain, especially neuropathic pain.

The patient to be treated prophylactically or therapeutically with the method of the invention is preferably a mammal, for example a human or a nonhuman mammal or a nonhuman transgenic mammal. Specifically it is a human.

The compounds of the general formula I and their pharmaceutically acceptable salts as detailed above can be prepared by a skilled worker with knowledge of the technical teaching of the invention in implementing and/or in analogous implementation of process steps known per se.

The compounds I and/or their pharmaceutically acceptable salts, N-oxides and their stereoisomers are distinguished by having a selectivity for the vasopressin V1b receptor subtype vis-à-vis at least one of the closely related vasopressin/oxytocin receptor subtypes (for example vasopressin V1a, vasopressin V2 and/or oxytocin).

Alternatively, or preferably in addition, the compounds I and/or their pharmaceutically acceptable salts, N-oxides and a stereoisomers are distinguished by having an improved metabolic stability.

The metabolic stability of a compound can be measured for example by incubating a solution of this compound with liver microsomes from particular species (for example rat, dog or human) and determining the half-life of the compound under these conditions (RS Obach, Curr Opin Drug Discov Devel. 2001, 4, 36-44). It is possible in this connection to conclude from an observed longer half-life that the metabolic stability of the compound is improved. The stability in the presence of human liver microsomes is of particular interest because it makes it possible to predict the metabolic degradation of the compound in the human liver. Compounds with increased metabolic stability (measured in the liver microsome test) are therefore probably also degraded more slowly in the liver. The slower metabolic degradation in the liver may lead to higher and/or longer-lasting concentrations (active levels) of the compound in the body, so that the elimination half-life of the compounds of the invention is increased. Increased and/or longer-lasting active levels may lead to a better activity of the compound in the treatment or prophylaxis of various vasopressin-related diseases. In addition, an improved metabolic stability may lead to an increased bioavailability after oral administration, because the compound is subject, after absorption in the intestine, to less metabolic degradation in the liver (so-called first pass effect). An increased oral bioavailability may, owing to an increased concentration (active level) of the compound, lead to a better activity of the compound after oral administration.

The compounds of the invention are effective after administration by various routes. Possible examples are intravenous, intramuscular, subcutaneous, topical, intratracheal, intranasal, transdermal, vaginal, rectal, sublingual, buccal or oral administration, and administration is frequently intravenous, intramuscular or, in particular, oral.

The present invention also relates to pharmaceutical compositions which comprise an effective dose of a compound I of the invention and/or an N-oxide, a stereoisomer and/or a pharmaceutically acceptable salt thereof and suitable pharmaceutical carriers (drug carriers).

These drug carriers are chosen according to the pharmaceutical form and the desired mode of administration and are known in principle to the skilled worker.

The compounds of the invention of the formula I, their N-oxides, steroisomers or optionally suitable salts of these compounds can be used to produce pharmaceutical compositions for oral, sublingual, buccal, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, vaginal or rectal administration, and be administered to animals or humans in uniform administration forms, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases.

The suitable administration forms (dose units) include forms for oral administration such as tablets, gelatin capsules, powders, granules and solutions or suspensions for oral intake, forms for sublingual, buccal, intratracheal or intranasal administration, aerosols, implants, forms of subcutaneous, intramuscular or intravenous administration and forms of rectal administration.

The compounds of the invention can be used in creams, ointments or lotions for topical administration.

In order to achieve the desired prophylactic or therapeutic effect, the dose of the active ingredient can vary between 0.01 and 50 mg per kg of body weight and per day.

Each unit dose may comprise from 0.05 to 5000 mg, preferably 1 to 1000 mg, of the active ingredient in combination with a pharmaceutical carrier. This unit dose can be administered once to 5 times a day, so that a daily dose of from 0.5 to 25 000 mg, preferably 1 to 5000 mg, is administered.

If a solid composition is prepared in the form of tablets, the active ingredient is mixed with a solid pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, silicon dioxide or the like.

The tablets can be coated with sucrose, a cellulose derivative or another suitable substance or be treated otherwise in order to display a sustained or delayed activity and to release a predetermined amount of the active ingredient continuously.

A preparation in the form of gelatin capsules is obtained by mixing the active ingredient with an extender and including the resulting mixture in soft or hard gelatin capsules.

A preparation in the form of a syrup or elixir or for administration in the form of drops may contain active ingredients together with a sweetener, which is preferably calorie-free, methylparaben or propylparaben as antiseptics, a flavoring and a suitable coloring substance.

Water-dispersible powders or granules may comprise the active ingredients mixed with dispersants, wetting agents or suspending agents, such as polyvinylpyrrolidones, and sweeteners or masking flavors.

Rectal or vaginal administration is achieved by using suppositories which are prepared with binders which melt at rectal temperature, for example cocoa butter or polyethylene glycols. Parenteral administration is effected by using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which comprise pharmacologically acceptable dispersants and/or wetting agents, for example propylene glycol or polyethylene glycol.

The active ingredient may also be formulated as microcapsules or centrosomes, if suitable with one or more carriers or additives.

The compositions of the invention may, in addition to the compounds of the invention, comprise other active ingredients which may be beneficial for the treatment of the disorders or diseases indicated above.

The present invention thus further relates to pharmaceutical compositions in which a plurality of active ingredients are present together, where at least one of these is a compound I of the invention, or salt thereof.

The invention is explained in more detail below by means of examples, but the examples are not to be understood to be restrictive.

The compounds of the invention can be prepared by various synthetic routes. The methods mentioned, as described accordingly in synthesis scheme 1, are explained in greater detail merely by way of example using the given examples without being exclusively restricted to synthesis route 1 or analogous methods.

EXPERIMENTAL SECTION

The compounds were either characterized via proton-NMR in d₆-dimethylsulfoxide or d-chloroform on a 600 MHz NMR instrument (Bruker AVANCE), or by mass spectrometry, generally recorded via HPLC-MS in a fast gradient on C18-material (electrospray-ionisation (ESI) mode), or melting point.

The magnetic nuclear resonance spectral properties (NMR) refer to the chemical shifts (δ) expressed in parts per million (ppm). The relative area of the shifts in the ¹H-NMR spectrum corresponds to the number of hydrogen atoms for a particular functional type in the molecule. The nature of the shift, as regards multiplicity, is indicated as singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint.), multiplet (m), doublet of doublets (dd), doublet of doublet of doublets (ddd), doublet of triplets (dt), triplet of doublets (td), triplet of triplets (tt) or quartet of doublets (qd). See also below abbreviations.

Abbreviations used:

THF: Tetrahydrofuran

DMSO: Dimethyl sulfoxide TFA: Trifluoroacetic acid p: pseudo (for example pt pseudo triplet) b or br.: broad (for example bs broad singlet) sym. symmetric s: singlet d: doublet t: triplet m: multiplet dd: doublet of doublets ddd doublet of doublet of doublets dt: doublet of triplets td triplet of doublets tt: triplet of triplets qd quartet of doublets

I. Preparation of the Starting Compounds a.) Synthesis of 1-(1-(oxetan-3-yl)-piperidin-4-yl)-piperazine (trifluoroacetic acid salt) a.1) Synthesis of tert-butyl 4-(1-(oxetan-3-yl)-piperidin-4-yl)-piperazine-1-carboxylate

In a 100 ml round-bottom flask 2 g (7.42 mmol) of 1-boc-4-(piperidin-4-yl)-piperazine and 1.07 g (14.85 mmol) of 3-oxetanone were dissolved in 30 ml of dichloromethane. 3.16 g (22.27 mmol) of sodium sulfate were added and the reaction was stirred for 10 min. Subsequently, 2.203 g (10.39 mmol) of sodium triacetoxyborohydride were added and the reaction was stirred for 5 min. pH was adjusted to 5-6 with acetic acid and the reaction was stirred over night. Then, 50 ml of water were added and the resulting two phases were separated. The organic phase was washed twice with water dried over MgSO₄, filtered and evaporated. The resulting solid was digested in methyl-tert-butyl ether, filtered off, washed with 10 ml of methyl-tert-butyl ether and dried. Flash chromatography (silica gel/gradient from 0 to 20% methanol in dichloromethane) yielded 650 mg of the title compound as a yellowish solid.

a.2) Synthesis of 1-(1-(oxetan-3-yl)-piperidin-4-yl)-piperazine (trifluoroacetic acid salt)

In a 100 ml round-bottom flask 1.63 g (5.01 mmol) of tert-butyl 4-(1-(oxetan-3-yl)-piperidin-4-yl)-piperazine-1-carboxylate were dissolved in 5 ml of dichloromethane. 3 ml (38.9 mmol) of trifluoroacetic acid were added and the reaction was stirred for 30 min. The solution was concentrated and digested in 40 ml of methyl-tert-butyl ether. The solid was filtered and washed with 20 ml of methyl-tert-butyl ether to yield 2.79 of the title compound as a white solid.

b.) Synthesis of 1-(oxetan-3-yl)-4-(piperidin-4-yl)piperazine, (trifluoroacetic acid salt)

The compound was synthesized in analogy to a.), using however 1-boc-4-(piperazin-4-yl)-piperidine as starting amine compound and NaBH₃CN/ZnCl as reduction agent.

c) Synthesis of 1-(oxetan-3-yl)-4,4′-bipiperidine c.1) Synthesis of benzyl 1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxylate

The compound was synthesized in analogy to a), using however benzyl[4,4′-bipieridine]-1-carboxylate as starting amine compound.

c.2) Synthesis of 1-(oxetan-3-yl)-4,4′-bipiperidine

520 mg (1.45 mmol) of benzyl 1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxylate was dissolved in 30 ml methanol and hydrogenated in the H-cube® flow hydrogenator using a 10 mol % Pd (C) cartridge at a flow rate of 1 ml/min. The solvent was removed in vacuo providing 372 mg of the title compound which was used without further purification.

II. Preparation of the Compounds of the Formula I

Enantiomers of the compounds I were prepared by using enantiomerically pure starting compounds.

Example 1 (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-61 of Table A)

Route A

In a 100 ml 3-necked flask, 100 mg (0.163 mmol) of (S)-phenyl(5-cyano-1-((2,4-dimethoxyphenyl)-sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-carbamate was stirred in THF for 5 min. 111 mg (0.195 mmol) of 1-(1-(oxetan-3-yl)piperidin-4-yl)-piperazine (used as trifluoroacetic acid salt) and 82 mg (0.814 mmol) of triethylamine were added and the reaction was stirred over night at room temperature. The solvent was removed, dichloromethane was added and the solution was extracted with water. The organic phase was washed with aqueous Na₂CO₃, dried over MgSO₄ and the solvent was removed. The resulting crude product was subjected to flash chromatography (silica gel/dichloromethane: methanol=90:10) to yield 98.2 mg (81%) of the title compound.

Route B B. 1) (S)-tert-butyl 4-(4-((5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)carbamoyl)piperazin-1-yl)piperidine-1-carboxylate

The compound was synthesized in analogy to Route A) using 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)piperazine as amine compound.

B.2) (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(piperidin-4-yl)piperazine-1-carboxamide

To a solution of 2.53 g (3.20 mmol) of (S)-tert-butyl 4-(4-((5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)carbamoyl)piperazin-1-yl)piperidine-1-carboxylate in DCM (35 ml) was added 2.5 mL trifluoroacetic acid (32.4 mmol) and the reaction mixture was stirred overnight. The solvent was removed in vacuo and the residue was taken up in water/EtOAc (70 ml/70 ml). After neutralization with sat. aqueous NaHCO3

solution (20 ml), the organic phase was separated and the aqueous phase extracted with EtOAc. The combined organic layers werde washed with brine and dried (MgSO4). Purification by flash chromatography (silica, DCM/MeOH gradient 0-100% MeOH) provided 1 g (36%) of the title compound as colorless solid.

B.3) (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

In a 100 ml 3-necked flask, 100 mg (0.145 mmol) of (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(piperidin-4-yl)-piperazine-1-carboxamide were stirred in 4 ml of dichloromethane. 10.45 mg (0.145 mmol) of oxetan-3-one dissolved in 2 ml of dichloromethane were added and the mixture was stirred for 5 min. 30.7 mg of Na₂SO₄ were added and the mixture was stirred for another 5 min. 17.41 mg of acetic acid were added and the reaction was stirred for another 30 min. 46.1 mg (0.217 mmol) of sodium triacetoxyhydroborate were added and the reaction was stirred overnight. 1 ml of 2N NaOH and then 7 ml of water were added and the mixture was extracted thrice with ethylacetate and water. The organic phase was died over MgSO₄ and the solvent was removed. The resulting crude product was subjected to flash chromatography (silica gel/gradient from 0 to 5% methanol in dichloromethane) to yield 26.4 mg (24.4%) of the title compound.

ESI-MS [M+H⁺]=746.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.13 (m, 1H), 7.88 (d, 1H), 7.86 (d, 1H), 7.83-7.81 (m, 1H), 7.74-7.73 (m, 1H), 7.69 (s, 1H), 7.68 (d, 1H), 7.04-7.02 (m, 1H), 6.70-6.66 (m, 2H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 4.19-4.10 (m, 2H), 3.85 (s, 3H), 3.44 (s, 3H), 3.34-3.29 (m, 1H), 3.20 (m, 4H), 2.71-2.69 (m, 2H), 2.36-2.35 (m, 4H), 2.18-2.14 (m, 1H), 1.71-1.66 (m, 4H), 1.41-1.35 (m, 2H), 1.06 (t, 3H).

Example 2 (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.2, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 (or 31) and R¹, R², R³, R⁶ and R⁷ correspond to row A-61 of Table A)

The compound was prepared in analogy to route B of example 1.

ESI-MS [M+H⁺]=704.3;

¹H-NMR (600 MHz DMSO-d₆), δ [ppm]: 8.14-8.13 (m, 1H), 7.88 (d, 1H), 7.87 (d, 1H), 7.83 (m, 1H), 7.74-7.72 (m, 1H), 7.70 (s, 1H), 7.68 (d, 1H), 7.04-7.02 (m, 1H), 6.69-6.66 (m, 2H), 4.52-4.49 (m, 2H), 4.40-4.38 (m, 2H), 4.21-4.11 (m, 2H), 3.85 (s, 3H), 3.84-3.79 (m, 2H), 3.43 (s, 3H), 3.34 (m, 1H), 2.66-2.56 (m, 2H), 2.47-2.15 (m, 9H), 1.65-1.58 (m, 2H), 1.20-1.10 (m, 2H), 1.08 (t, 3H).

Example 3 N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(Compound of formula I.1, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-13 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=716.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.13-8.12 (m, 1H), 7.98-7.94 (m, 3H), 7.86 (d, 1H), 7.82-7.81 (m, 1H), 7.73 (s, 1H), 7.61 (d, 1H), 7.16-7.13 (m, 2H), 7.08-7.06 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 4.10-4.06 (m, 1H), 4.02-3.97 (m, 1H), 3.84 (s, 3H), 3.34-3.28 (m, 1H), 3.17 (m, 4H), 2.71-2.69 (m, 2H), 2.35 (m, 4H), 2.19-2.15 (m, 1H), 1.71-1.67 (m, 4H), 1.41-1.35 (m, 2H), 0.98 (t, 3H).

Example 4 N-(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)indolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(Compound of formula I.1, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-1 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=686.1;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.13 (m, 1H), 8.06-8.04 (m, 2H), 7.99-7.97 (m, 1H), 7.87 (d, 1H), 7.84-7.82 (m, 1H), 7.79-7.77 (m, 1H), 7.75 (s, 1H), 7.66-7.62 (m, 3H), 7.09-7.07 (m, 1H), 4.52-4.49 (m, 2H), 4.41-4.37 (m, 2H), 4.11-4.06 (m, 1H), 3.98-3.93 (m, 1H), 3.34-3.28 (m, 1H), 3.28 (m, 4H), 2.71-2.69 (m, 2H), 2.35 (m, 4H), 2.19-2.15 (m, 1H), 1.74-1.67 (m, 4H), 1.44-1.35 (m, 2H), 0.96 (t, 3H).

Example 5 (S)—N-(5-cyano-1-((4-cyanophenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-14 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=711.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.18-8.13 (m, 5H), 8.08-8.06 (m, 1H), 7.92 (d, 1H), 7.85-7.84 (m, 1H), 7.77 (s, 1H), 7.60 (d, 1H), 7.13-7.10 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 4.11-4.07 (m, 2H), 3.34-3.30 (m, 1H), 3.09 (m, 4H), 2.71-2.69 (m, 2H), 2.32 (m, 4H), 2.19-2.17 (m, 1H), 1.71-1.66 (m, 4H), 1.41-1.37 (m, 2H), 1.05 (t, 3H).

Example 6 (S)—N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((2-fluoro-4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-29 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=734.0;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.13 (m, 1H), 7.99-7.97 (m, 1H), 7.94-7.88 (m, 2H), 7.84-7.83 (m, 1H), 7.71 (s, 1H), 7.62-7.61 (m, 1H), 7.10-7.07 (m, 1H), 7.06-7.04 (m, 1H), 6.97-6.95 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 4.14-4.08 (m, 2H), 3.85 (s, 3H), 3.34-3.29 (m, 1H), 3.16-3.13 (m, 4H), 2.71-2.69 (m, 2H), 2.34 (m, 4H), 2.18-2.14 (m, 1H), 1.71-1.65 (m, 4H), 1.43-1.35 (m, 2H), 1.03 (t, 3H).

Example 7 N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(Compound of formula I.1, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-2083 of Table A) The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=764.3

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.17-8.14 (m, 1H), 7.89 (d, 1H), 7.82-7.81 (m, 1H), 7.72-7.69 (m, 3H), 7.06-7.04 (m, 1H), 6.71-6.68 (m, 2H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 4.19-4.11 (m, 2H), 3.86 (s, 3H), 3.50 (s, 3H), 3.34-3.29 (m, 1H), 3.19 (m, 4H), 2.71-2.69 (m, 2H), 2.34 (m, 4H), 2.18-2.14 (m, 1H), 1.71-1.66 (m, 4H), 1.40-1.34 (m, 2H), 1.08 (t, 3H)

Example 7A (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-2083 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=764.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.15-8.14 (m, 1H), 7.87 (d, 1H), 7.82-7.81 (m, 1H), 7.71-7.69 (m, 3H), 7.06-7.04 (m, 1H), 6.71-6.68 (m, 2H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 4.19-4.11 (m, 2H), 3.86 (s, 3H), 3.51 (s, 3H), 3.35-3.30 (m, 1H), 3.19 (m, 4H), 2.71-2.69 (m, 2H), 2.35 (m, 4H), 2.18-2.14 (m, 1H), 1.71-1.66 (m, 4H), 1.41-1.35 (m, 2H), 1.08 (t, 3H).

Example 8 (S)—N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((5-fluoro-2,4-dimethoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-270 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=764.0;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.13 (m, 1H), 7.88 (d, 1H), 7.85-7.83 (m, 2H), 7.72-7.70 (m, 2H), 7.67-7.66 (m, 1H), 7.08-7.05 (m, 1H), 6.90 (d, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 4.19-4.09 (m, 2H), 3.95 (s, 3H), 3.51 (s, 3H), 3.34-3.28 (m, 1H), 3.19 (m, 4H), 2.71-2.69 (m, 2H), 2.35 (m, 4H), 2.18-2.14 (m, 1H), 1.71-1.66 (m, 4H), 1.41-1.35 (m, 2H), 1.06 (t, 3H)

Example 9 (S)—N-(1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-2757 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=757.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.15-8.12 (m, 1H), 7.87 (d, 1H), 7.66-7.62 (m, 3H), 7.37-7.34 (m, 1H), 7.01-6.99 (m, 1H), 6.70-6.66 (m, 2H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 4.21-4.13 (m, 2H), 3.86 (s, 3H), 3.48 (s, 3H), 3.34-3.29 (m, 1H), 3.20 (m, 4H), 2.70-2.69 (m, 2H), 2.35 (m, 4H), 2.18-2.14 (m, 1H), 1.71-1.66 (m, 4H), 1.41-1.35 (m, 2H), 1.10 (t, 3H).

Example 10 (S)—N-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-1409 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=755.5;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.12-8.11 (m, 1H), 7.88 (d, 1H), 7.69 (d, 1H), 7.63 (s, 1H), 7.58-7.56 (m, 1H), 7.39-7.37 (m, 2H), 6.99-6.97 (m, 1H), 6.70-6.66 (m, 2H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 4.22-4.12 (m, 2H), 3.86 (s, 3H), 3.45 (s, 3H), 3.34-3.28 (m, 1H), 3.21 (m, 4H), 2.71-2.69 (m, 2H), 2.36 (m, 4H), 2.18-2.15 (m, 1H), 1.71-1.67 (m, 4H), 1.41-1.35 (m, 2H), 1.11 (t, 3H).

Example 11 (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxamide

(S-Enantiomer of the compound of formula I.3, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 (or 61) and R¹, R², R³, R⁶ and R⁷ correspond to row A-61 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=745.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.11 (m, 1H), 7.88-7.87 (m, 2H), 7.83-7.80 (m, 1H), 7.72-7.71 (m, 1H), 7.68-7.64 (m, 2H), 7.04-7.00 (m, 1H), 6.70-6.68 (m, 1H), 6.66 (d, 1H), 4.52 (m, 2H), 4.41 (m, 2H), 4.21-4.11 (m, 2H), 3.85 (s, 3H), 3.83 (m, 2H), 3.48 (s, 3H), 3.35 (m, 1H), 2.71 (m, 2H), 2.57 (m, 2H), 1.70-1.52 (m, 6H), 1.17 (m, 3H), 1.07 (t, 3H), 1.02 (m, 1H), 0.93-0.90 (m, 2H).

Example 12 (S)—N-(5-cyano-1-((4-cyanophenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.2, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 (or 31) and R¹, R², R³, R⁶ and R⁷ correspond to row A-14 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=711.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.17-8.12 (m, 5H), 8.07-8.05 (m, 1H), 7.93 (d, 1H), 7.85-7.83 (m, 1H), 7.74 (s, 1H), 7.60 (m, 1H), 7.13-7.10 (m, 1H), 4.52-4.49 (m, 2H), 4.41-4.39 (m, 2H), 4.12-4.08 (m, 2H), 3.72-3.63 (m, 2H), 3.38-3.32 (m, 1H), 2.58-2.56 (m, 2H), 2.46-2.23 (m, 9H), 1.65-1.59 (m, 2H), 1.14-1.10 (m, 2H), 1.06 (t, 3H).

Example 13 (S)—N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.2, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 (or 31) and R¹, R², R³, R⁶ and R⁷ correspond to row A-13 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=716.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.12 (m, 1H), 7.97-7.93 (m, 3H), 7.87 (d, 1H), 7.82-7.80 (m, 1H), 7.73 (s, 1H), 7.62 (d, 1H), 7.15-7.13 (m, 2H), 7.08-7.06 (m, 1H), 4.51-4.49 (m, 2H), 4.40-4.38 (m, 2H), 4.12-4.07 (m, 1H), 4.04-3.99 (m, 1H), 3.84 (s, 3H), 3.77 (m, 2H), 3.34 (m, 1H), 2.61 (m, 2H), 2.47-2.22 (m, 9H), 1.65-1.60 (m, 2H), 1.17-1.12 (m, 2H), 1.00 (t, 3H).

Example 14 (S)—N-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.2, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 (or 31) and R¹, R², R³, R⁶ and R⁷ correspond to row A-1409 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=756.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.12 (m, 1H), 7.87 (d, 1H), 7.71-7.69 (m, 1H), 7.65 (s, 1H), 7.57-7.56 (m, 1H), 7.38-7.36 (m, 2H), 6.99-6.97 (m, 1H), 6.69-6.68 (m, 1H), 6.66 (d, 1H), 4.52-4.50 (m, 2H), 4.40-4.38 (m, 2H), 4.22-4.15 (m, 2H), 3.85 (m, 5H), 3.44 (s, 3H), 3.34 (m, 1H), 2.62 (m, 3H), 2.52-2.22 (m, 8H), 1.63 (m, 2H), 1.16 (m, 2H), 1.13 (t, 3H).

Example 15 N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(Compound of formula I.4, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-61 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=732.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.15-8.14 (m, 1H), 7.91-7.87 (m, 2H), 7.81-7.80 (m, 1H), 7.75-7.74 (m, 1H), 7.71-7.68 (m, 2H), 7.05-7.04 (m, 1H), 6.71-6.70 (m, 1H), 6.68 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 3.86 (s, 3H), 3.70 (s, 3H), 3.49 (s, 3H), 3.35-3.29 (m, 1H), 3.20 (m, 4H), 2.71-2.69 (m, 2H), 2.35 (m, 4H), 2.18-2.14 (m, 1H), 1.74-1.66 (m, 4H), 1.46-1.37 (m, 2H).

Example 16 N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide

(Compound of formula I.5, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 (or 31) and R¹, R², R³, R⁶ and R⁷ correspond to row A-61 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=732.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.15-8.14 (m, 1H), 7.90-7.87 (m, 2H), 7.81-7.79 (m, 1H), 7.73-7.68 (m, 3H), 7.05-7.03 (m, 1H), 6.70-6.67 (m, 2H), 4.52-4.49 (m, 2H), 4.40-4.38 (m, 2H), 3.86 (s, 3H), 3.83-3.81 (m, 2H), 3.72 (s, 3H), 3.48 (s, 3H), 3.34 (m, 1H), 2.64-2.61 (m, 2H), 2.50-2.23 (m, 9H), 1.61 (m, 2H), 1.16 (m, 2H).

Example 17 N—((S)-5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-((1S,4S)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.2, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 47 and R¹, R², R³, R⁶ and R⁷ correspond to row A-61 of Table A)

The compound was prepared in analogy to route B of example 1.

ESI-MS [M+H⁺]=758.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.13-8.12 (m, 1H), 7.88-7.87 (m, 2H), 7.83-7.81 (m, 1H), 7.73-7.71 (m, 1H), 7.68 (d, 1H), 7.66 (m, 1H), 7.03-7.01 (m, 1H), 6.67-6.68 (m, 1H), 6.66-6.65 (m, 1H), 4.56-4.54 (m, 1H), 4.51-4.49 (m, 1H), 4.34-4.31 (m, 2H), 4.19-4.10 (m, 2H), 3.85 (s, 3H), 3.81-3.79 (m, 1H), 3.66 (m, 2H), 3.53 (m, 5H), 2.71 (m, 4H), 2.41 (m, 2H), 2.30 (m, 1H), 1.65 (m, 1H), 1.53 (m, 3H), 1.07-1.06 (m, 5H).

Example 18 (S)—N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxy-2,3-dimethylphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-208 of Table A)

The compound was prepared in analogy to route A of example 1.

ESI-MS [M+H⁺]=744.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.15-8.14 (m, 1H), 8.08 (d, 1H), 7.86-7.85 (m, 1H), 7.83-7.81 (m, 1H), 7.79 (d, 1H), 7.75 (s, 1H), 7.68-7.67 (m, 1H), 7.07-7.05 (m, 2H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 4.19-4.09 (m, 2H), 3.89 (s, 3H), 3.35-3.30 (m, 1H), 3.22 (m, 4H), 2.71-2.69 (m, 2H), 2.39-2.36 (m, 7H), 2.19-2.15 (m, 1H), 2.09 (s, 3H), 1.71-1.66 (m, 4H), 1.41-1.35 (m, 2H), 0.98 (t, 3H).

Example 19 (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-ylmethyl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.61, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-61 of Table A)

The compound was prepared in analogy to route B of example 1, using however oxetane-3-carbaldehyde.

Example 20

N-[(3S)-1-(benzenesulfonyl)-5-cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[4-(oxetan-3-yl)piperazin-1-yl]piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.2, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 (or 31) and R¹, R², R³, R⁶ and R⁷ correspond to row A-1 of Table A)

ESI-MS [M+H⁺]=686.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.13 (m, 1H), 8.06-8.04 (m, 2H), 7.98-7.96 (m, 1H), 7.87 (d, 1H), 7.83-7.82 (m, 1H), 7.80-7.76 (m, 2H), 7.66-7.63 (m, 3H), 7.09-7.07 (m, 1H), 4.52-4.49 (m, 2H), 4.40-4.38 (m, 2H), 4.11-4.08 (m, 1H), 4.00-3.95 (m, 1H), 3.78-3.76 (m, 2H), 3.34 (m, 1H), 2.61 (m, 2H), 2.50-2.15 (m, 9H), 1.72-1.60 (m, 2H), 1.23-1.12 (m, 2H), 0.97 (t, 3H).

Example 21 N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-61 of Table A)

ESI-MS [M+H⁺]=732.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.15-8.14 (m, 1H), 7.90 (d, 1H), 7.87 (d, 1H), 7.81-7.80 (m, 1H), 7.75-7.73 (m, 1H), 7.71 (s, 1H), 7.68 (m, 1H), 7.05-7.03 (m, 1H), 7.71-7.69 (m, 1H), 6.67 (d, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 3.86 (s, 3H), 3.70 (s, 3H), 3.49 (s, 3H), 3.34-3.29 (m, 1H), 3.20 (m, 4H), 2.71-2.69 (m, 2H), 2.35 (m, 4H), 2.18-2.14 (m, 1H), 1.71-1.66 (m, 4H), 1.41-1.36 (m, 2H).

Example 22 N-[(3S)-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-5,6-difluoro-2-oxo-indolin-3-yl]-4-[4-(oxetan-3-yl)piperazin-1-yl]piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.2, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 (or 31) and R¹, R², R³, R⁶ and R⁷ correspond to row A-2757 of Table A)

ESI-MS [M+H⁺]=757.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.15-8.12 (m, 1H), 7.87 (d, 1H), 7.67-7.62 (m, 3H), 7.38-7.34 (m, 1H), 7.01-6.99 (m, 1H), 6.70-6.67 (m, 2H), 4.52-4.49 (m, 2H), 4.42-4.38 (m, 2H), 4.22-4.13 (m, 2H), 3.85 (s, 3H), 3.85-3.81 (m, 2H), 3.47 (s, 3H), 3.34 (m, 1H), 2.64-2.60 (m, 2H), 2.49-2.22 (m, 9H), 1.64-1.62 (m, 2H), 1.17-1.12 (m, 2H), 1.12 (t, 3H).

Example 23 N-[(3R)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(R-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-13 of Table A)

ESI-MS [M+H⁺]=716.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.13-8.12 (m, 1H), 7.97-7.94 (m, 3H), 7.87 (m, 1H), 7.82-7.81 (m, 1H), 7.79 (s, 1H), 7.61 (m, 1H), 7.17-7.14 (m, 2H), 7.08-7.06 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 4.11-4.06 (m, 1H), 4.01-3.98 (m, 1H), 3.84 (s, 3H), 3.17 (s, 3H), 2.71-2.69 (m, 2H), 2.35 (m, 4H), 2.19-2.15 (m, 1H), 1.71-1.67 (m, 4H), 1.41-1.33 (m, 2H), 1.26 (m, 2H), 0.98 (t, 3H).

Example 24 N-[(3S)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-13 of Table A)

ESI-MS [M+H⁺]=716.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.13-8.12 (m, 1H), 7.97-7.94 (m, 3H), 7.86 (m, 1H), 7.82-7.81 (m, 1H), 7.73 (s, 1H), 7.61 (m, 1H), 7.15-7.14 (m, 2H), 7.08-7.06 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 4.11-4.06 (m, 1H), 4.02-3.98 (m, 1H), 3.81 (s, 3H), 3.17 (s, 3H), 2.73-2.69 (m, 2H), 2.35 (m, 4H), 2.19-2.15 (m, 1H), 1.71-1.67 (m, 4H), 1.41-1.33 (m, 2H), 1.23 (m, 2H), 0.98 (t, 3H).

Example 25 N-[(3S)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-[(5-methoxy-2-pyridyl)sulfonyl]-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.19, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row B-4 of Table B)

ESI-MS [M+H⁺]=717.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.41-8.40 (d, 1H), 8.16-8.15 (d, 1H), 8.14-8.13 (m, 1H), 7.94-7.92 (m, 2H), 7.85-7.83 (m, 1H), 7.73 (s, 1H), 7.66-7.64 (m, 1H), 7.62 (d, 1H), 7.08-7.06 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 4.10-4.02 (m, 2H), 3.91 (s, 3H), 3.34-3.29 (m, 1H), 3.15 (m, 4H), 2.71-2.69 (m, 2H), 2.35 (m, 4H), 2.20-2.15 (m, 1H), 1.71-1.67 (m, 4H), 1.42-1.36 (m, 2H), 1.02 (t, 3H).

Example 26 N-[(3S)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-59 of Table A)

ESI-MS [M+H⁺]=734.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.15-8.13 (m, 1H), 8.02-7.99 (m, 1H), 7.90-7.83 (m, 3H), 7.70 (s, 1H), 7.66 (d, 1H), 7.18-7.15 (m, 1H), 7.08-7.06 (m, 1H), 6.99-6.96 (m, 1H), 4.51-4.48 (m, 2H), 4.39-4.37 (m, 2H), 4.18-4.10 (m, 2H), 3.47 (s, 3H), 3.34-3.29 (m, 1H), 3.18 (m, 4H), 2.70-2.69 (m, 2H), 2.34 (m, 4H), 2.19-2.14 (m, 1H), 1.71-1.65 (m, 4H), 1.40-1.34 (m, 2H), 1.06 (t, 3H).

Example 27 N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.6, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 (or 61) and R¹, R², R³, R⁶ and R⁷ correspond to row A-61 of Table A)

ESI-MS [M+H⁺]=731.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.15-8.14 (m, 1H), 7.90-7.87 (m, 2H), 7.81-7.80 (m, 1H), 7.73-7.72 (m, 1H), 7.68-7.67 (m, 2H), 7.05-7.03 (m, 1H), 6.70-6.68 (m, 1H), 6.67 (d, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 3.86 (s, 3H), 3.83 (m, 2H), 3.72 (s, 3H), 3.48 (s, 3H), 3.32-3.27 (m, 1H), 2.70-2.69 (m, 2H), 2.57-2.52 (m, 2H), 1.65-1.61 (m, 2H), 1.56-1.50 (m, 4H), 1.20-1.10 (m, 3H), 1.01-0.88 (m, 3H).

Example 28 N-[(3S)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-11 of Table A)

ESI-MS [M+H⁺]=704.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.15-8.14 (m, 1H), 8.12-8.08 (m, 2H), 8.04-8.02 (m, 1H), 7.91-7.90 (d, 1H), 7.84-7.82 (m, 1H), 7.75 (s, 1H), 7.61 (d, 1H), 7.51-7.47 (m, 2H), 7.11-7.09 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 4.12-4.01 (m, 2H), 3.35-3.28 (m, 1H), 3.14 (m, 4H), 2.71-2.69 (m, 2H), 2.34 (m, 4H), 2.19-2.15 (m, 1H), 1.71-1.66 (m, 4H), 1.41-1.35 (m, 2H), 1.01 (t, 3H).

Example 29 N-[(3S)-5-cyano-3-(2-methoxy-3-pyridyl)-1-[(5-methoxy-2-pyridyl)sulfonyl]-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.22, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row B-4 of Table B)

ESI-MS [M+H⁺]=703.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.45 (m, 1H), 8.21-8.19 (d, 1H), 8.15-8.14 (m, 1H), 7.93-7.90 (m, 2H), 7.83-7.82 (m, 1H), 7.77 (s, 1H), 7.68-7.66 (m, 1H), 7.65 (d, 1H), 7.10-7.08 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 3.92 (s, 3H), 3.54 (s, 3H), 3.34-3.29 (m, 1H), 3.19 (m, 4H), 2.71-2.69 (m, 2H), 2.39-2.36 (m, 4H), 2.20-2.16 (m, 1H), 1.71-1.68 (m, 4H), 1.42-1.38 (m, 2H).

Example 30 N-[(3S)-5-cyano-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-59 of Table A)

ESI-MS [M+H⁺]=720.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.16-8.15 (m, 1H), 8.05-8.02 (m, 1H), 7.89-7.87 (m, 2H), 7.83-7.81 (m, 1H), 7.73 (s, 1H), 7.68 (m, 1H), 7.19-7.17 (m, 1H), 7.10-7.08 (m, 1H), 7.00-6.97 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 3.70 (s, 3H), 3.52 (s, 3H), 3.34-3.29 (m, 1H), 3.19 (m, 4H), 2.71-2.69 (m, 2H), 2.34 (m, 4H), 2.16 (m, 1H), 1.71-1.65 (m, 4H), 1.39-1.36 (m, 2H).

Example 31 N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[4-(oxetan-3-yl)piperazin-1-yl]piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.5, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 (or 31) and R¹, R², R³, R⁶ and R⁷ correspond to row A-61 of Table A)

ESI-MS [M+H⁺]=732.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.16-8.14 (m, 1H), 7.90-7.87 (m, 2H), 7.81-7.80 (m, 1H), 7.74-7.72 (m, 2H), 7.69-7.68 (m, 1H), 7.06-7.04 (m, 1H), 6.70-6.67 (m, 2H), 4.53-4.50 (m, 2H), 4.40-4.38 (m, 2H), 3.86 (s, 3H), 3.83-3.81 (m, 2H), 3.72 (s, 3H), 3.48 (s, 3H), 3.34 (m, 1H), 2.63-2.59 (m, 2H), 2.45 (m, 4H), 2.35-2.31 (m, 1H), 2.23 (m, 4H), 1.63-1.58 (m, 2H), 1.16 (m, 2H).

Example 32 N-[(3S)-5-cyano-3-(2-ethoxy-5-methoxy-phenyl)-1-[(5-methoxy-2-pyridyl)sulfonyl]-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.31, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row B-4 of Table B)

ESI-MS [M+H⁺]=746.3.

Example 33 N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-5-methoxy-phenyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.13, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-61 of Table A)

ESI-MS [M+H⁺]=775.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 7.88-7.86 (m, 2H), 7.80-7.78 (m, 1H), 7.68-7.67 (m, 1H), 7.63 (m, 1H), 6.91 (m, 3H), 6.69-6.67 (m, 1H), 6.64 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.38 (m, 2H), 3.97-3.92 (m, 1H), 3.85 (s, 3H), 3.79-3.74 (m, 1H), 3.70 (s, 3H), 3.45 (s, 3H), 3.34 (m, 1H), 3.17 (m, 4H), 2.71 (m, 2H), 2.36 (m, 4H), 2.17 (m, 1H), 1.70 (m, 4H), 1.39 (m, 2H), 1.12-1.09 (t, 3H).

Example 34 N-[(3S)-5-cyano-1-(4-methoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-13 of Table A)

ESI-MS [M+H⁺]=702.3.

Example 35 N-[(3S)-5-cyano-3-(2-ethoxy-5-methoxy-phenyl)-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.13, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-59 of Table A)

ESI-MS [M+H⁺]=763.3.

Example 36 N-[(3S)-5-cyano-1-(4-methoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.6, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 (or 61) and R¹, R², R³, R⁶ and R⁷ correspond to row A-13 of Table A)

ESI-MS [M+H⁺]=701.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.13 (m, 1H), 8.01-7.99 (m, 2H), 7.95-7.94 (m, 1H), 7.86-7.85 (m, 1H), 7.81-7.79 (m, 1H), 7.72 (s, 1H), 7.63-7.62 (m, 1H), 7.18-7.15 (m, 2H), 7.10-7.08 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 3.85 (m, 5H), 3.48 (s, 3H), 3.35-3.26 (m, 1H), 2.70-2.69 (m, 2H), 2.57 (m, 2H), 1.66-1.53 (m, 6H), 1.19-1.12 (m, 3H), 1.03-0.92 (m, 3H).

Example 37 N-[(3S)-5-cyano-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.6, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 (or 61) and R¹, R², R³, R⁶ and R⁷ correspond to row A-59 of Table A)

ESI-MS [M+H⁺]=719.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.16-8.15 (m, 1H), 8.04-8.02 (m, 1H), 7.90-7.88 (m, 1H), 7.87-7.86 (m, 1H), 7.83-7.81 (m, 1H), 7.69 (s, 1H), 7.68-7.67 (m, 1H), 7.19-7.16 (m, 1H), 7.10-7.08 (m, 1H), 6.99-6.96 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 3.82-3.80 (m, 2H), 3.71 (s, 3H), 3.50 (s, 3H), 3.31-3.27 (m, 1H), 2.70-2.68 (m, 2H), 2.52 (m, 2H), 1.65-1.61 (m, 2H), 1.56-1.50 (m, 4H), 1.18-1.10 (m, 3H), 1.00-0.89 (m, 3H).

Example 38 N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-5-[1-(oxetan-3-yl)-4-piperidyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 7 and R¹, R², R³, R⁶ and R⁷ correspond to row A-61 of Table A)

ESI-MS [M+H⁺]=758.3.

Example 39 N-[(3S)-5-cyano-3-(2-methoxy-3-pyridyl)-1-[(5-methoxy-2-pyridyl)sulfonyl]-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.24, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 (or 61) and R¹, R², R³, R⁶ and R⁷ correspond to row B-4 of Table B)

ESI-MS [M+H⁺]=702.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.45-8.44 (m, 1H), 8.20-8.19 (m, 1H), 8.15-8.14 (m, 1H), 7.92-7.90 (m, 2H), 7.83-7.81 (m, 1H), 7.73 (s, 1H), 7.68-7.66 (m, 1H), 7.65-7.64 (m, 1H), 7.10-7.08 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 3.92 (s, 3H), 3.83-3.81 (m, 2H), 3.55 (s, 3H), 3.35-3.27 (m, 1H), 2.70-2.68 (m, 2H), 2.56 (m, 2H), 1.66-1.62 (m, 2H), 1.60-1.54 (m, 4H), 1.19-1.12 (m, 3H), 1.03-0.92 (m, 3H).

Example 40 N-[(3S)-5-cyano-1-(4-fluorophenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.6, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 (or 61) and R¹, R², R³, R⁶ and R⁷ correspond to row A-11 of Table A)

ESI-MS [M+H⁺]=689.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.16-8.12 (m, 3H), 8.03-8.00 (m, 1H), 7.90-7.88 (m, 1H), 7.82-7.81 (m, 1H), 7.75 (s, 1H), 7.64 (m, 1H), 7.53-7.49 (m, 2H), 7.13-7.11 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 3.81 (m, 2H), 3.52 (s, 3H), 3.35-3.27 (m, 1H), 2.70-2.68 (m, 2H), 2.55 (m, 2H), 1.66-1.62 (m, 2H), 1.59-1.53 (m, 4H), 1.19-1.11 (m, 3H), 1.02-0.91 (m, 3H).

Example 41 N-[(3S)-5-cyano-1-(5-fluoro-2,4-dimethoxy-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-270 of Table A)

ESI-MS [M+H⁺]=750.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.16-8.15 (m, 1H), 7.88-7.86 (m, 1H), 7.86-7.84 (m, 1H), 7.82-7.80 (m, 1H), 7.76-7.74 (m, 2H), 7.68 (m, 1H), 7.09-7.07 (m, 1H), 6.92-6.91 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 3.95 (s, 3H), 3.71 (s, 3H), 3.55 (s, 3H), 3.35-3.29 (m, 1H), 3.19 (m, 4H), 2.71-2.69 (m, 2H), 2.34 (m, 4H), 2.19-2.14 (m, 1H), 1.71-1.66 (m, 4H), 1.41-1.36 (m, 2H).

Example 42 N-[(3S)-5-cyano-1-(5-fluoro-2,4-dimethoxy-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide

(S-Enantiomer of the compound of formula I.6, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 (or 61) and R¹, R², R³, R⁶ and R⁷ correspond to row A-270 of Table A)

ESI-MS [M+H⁺]=749.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.16-8.15 (m, 1H), 7.88-7.87 (m, 1H), 7.84-7.80 (m, 2H), 7.75-7.73 (m, 1H), 7.70 (s, 1H), 7.68-7.67 (m, 1H), 7.09-7.07 (m, 1H), 6.92-6.90 (m, 1H), 4.51-4.49 (m, 2H), 4.41-4.37 (m, 2H), 3.95 (s, 3H), 3.85-3.80 (m, 2H), 3.72 (s, 3H), 3.54 (s, 3H), 3.33-3.27 (m, 1H), 2.70-2.68 (m, 2H), 2.56 (m, 2H), 1.65-1.61 (m, 2H), 1.57-1.51 (m, 4H), 1.20-1.10 (m, 3H), 0.98-0.89 (m, 3H).

Example 43 N-[(3S)-5-cyano-1-(4-cyanophenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-14 of Table A)

ESI-MS: [M+H⁺]=697.25;

¹H NMR (CDCl₃, 600 MHz), δ [ppm]: 8.22 (d, 2H), 8.18 (dd, 1H), 8.05 (d, 1H), 7.80 (d, 2H), 7.67 (dd, 1H), 7.53-7.54 (m, 1H), 7.33 (dd, 1H), 6.93 (m sym., 1H), 6.55 (s, 1H), 4.65 (t, 2H), 4.60 (t, 2H), 4.07 (s, 3H), 3.44 (qd, 1H), 3.15-3.22 (m, 2H), 3.12 (br. s., 2H), 2.80 (d, 2H), 2.47 (br. s., 4H), 2.30 (br. s., 1H), 1.73-1.85 (m, 4H).

Example 44 N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-isopropoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.73, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-61 of Table A)

ESI-MS: [M+H⁺]=760.30.

Example 45 N-[(3S)-5-cyano-3-(2-methoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-12 of Table A)

ESI-MS: [M+H⁺]=686.20;

¹H NMR (CDCl₃, 600 MHz), δ [ppm]: 8.15 (dd, 1H), 7.99-8.02 (m, 3H), 7.61 (dd, 1H), 7.55 (d, 1H), 7.32 (d, 2H), 6.87 (dd, 1H), 6.59 (br. s., 1H), 4.63-4.66 (m, 2H), 4.60 (br. s, 2H), 4.05 (s, 3H), 3.44 (m sym., 1H), 3.24 (br. s., 2H), 3.20 (br. s., 2H), 2.81 (d, 2H), 2.48 (br. s., 3H), 2.42 (s, 3H), 2.31 (br. s., 1H), 1.76-1.83 (br. m., 4H).

Example 46 N-[(3S)-5-cyano-1-(2-methoxy-4-methyl-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-60 of Table A)

ESI-MS: [M+H⁺]=716.30;

¹H NMR (CDCl₃, 600 MHz), δ [ppm]: 8.14 (ddd, 1H), 8.09 (dd, 1H), 8.02 (d, 1H), 7.62 (t, 2H), 7.25-7.29 (m, incl. CHCl₃), 7.22 (d, 1H), 7.22 (d, 1H), 6.85 (dd, 1H), 6.74 (s, 1H), 6.64 (br. m, 1H), 4.65 (t, 2H), 4.59 (br. s, 2H), 4.08-4.10 (m, 3H), 3.52-3.54 (m, 3H), 3.44 (br. m, 1H), 3.23 (br. s., 4H), 2.80 (d, 2H), 2.47 (br. s., 3H), 2.39-2.41 (m, 3H), 2.30 (br. s., 1H), 1.74-1.82 (m, 4H).

Example 47 N-[(3S)-5-cyano-1-(4-cyano-2-fluoro-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-30 of Table A)

ESI-MS: [M+H⁺]=715.20;

¹H NMR (CDCl₃, 600 MHz), δ [ppm]: 8.29 (t, 1H), 8.18 (dd, 1H), 8.10 (d, 1H), 7.68 (dd, 1H), 7.60 (dd, 1H), 7.56 (s, 1H), 7.46 (dd, 1H), 7.33 (dd, 1H), 6.93 (m, 1H), 6.52 (br. s., 1H), 4.64 (t, 2H), 4.59 (br. m, 2H), 4.07 (s, 3H), 3.44 (quint, 1H), 3.19 (br. s, 2H), 3.10 (br. s., 2H), 2.80 (d, 2H), 2.46 (br. s., 4H), 2.30 (br. s., 1H), 1.74-1.82 (m, 4H).

Example 48 N-[(3S)-5-cyano-1-(2,4-difluorophenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-27 of Table A)

ESI-MS: [M+H⁺]=708.20;

¹H NMR (CDCl₃, 600 MHz), δ [ppm]: 8.16-8.21 [m, 2H, incl. 8.17 (d, 1H)], 8.11 (d, 1H), 7.67 (dd, 1H), 7.56 (d, 1H), 7.30 (d, 1H), 7.04 (td, 1H), 6.89-6.93 (m, 2H), 6.57 (br. s., 1H), 4.63-4.66 (m, 2H), 4.58-4.62 (m, 2H), 4.07 (s, 3H), 3.44 (br. s., 1H), 3.23 (br. s., 2H), 3.14 (br. s., 2H), 2.80 (d, 2H), 2.46 (br. s., 3H), 2.29 (br. s., 1H), 1.73-1.81 (m, 4H).

Example 49 (S)—N-(5-cyano-1-((2-methoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxamide

(S-Enantiomer of the compound of formula I.6, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 61 and R¹, R², R³, R⁶ and R⁷ correspond to row A-4 of Table A)

ESI-MS [M+H⁺]=701.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.16-8.14 (m, 1H), 8.00-7.98 (m, 1H), 7.90-7.88 (m, 1H), 7.83-7.81 (m, 1H), 7.77-7.75 (m, 1H), 7.72-7.69 (m, 3H), 7.23-7.21 (m, 1H), 7.16-7.13 (m, 1H), 7.06-7.04 (m, 1H), 4.51-4.49 (m, 2H), 4.39-4.37 (m, 2H), 3.84-3.82 (m, 2H), 3.70 (s, 3H), 3.50 (s, 3H), 3.31-3.26 (m, 1H), 2.70-2.68 (m, 2H), 2.57-2.52 (m, 2H), 1.65-1.50 (m, 6H), 1.18-1.11 (m, 3H), 1.04-0.88 (m, 3H).

Example 50 (S)—N-(5-cyano-3-(2-methoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)indolin-3-yl)-1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxamide

(S-Enantiomer of the compound of formula I.6, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 61 and R¹, R², R³, R⁶ and R⁷ correspond to row A-1 of Table A)

ESI-MS [M+H⁺]=671.3;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.13 (m, 1H), 8.10-8.08 (m, 2H), 7.99-7.98 (m, 1H), 7.88-7.86 (m, 1H), 7.82-7.78 (m, 2H), 7.75 (s, 1H), 7.68-7.66 (m, 2H), 7.64 (d, 1H), 7.11-7.09 (m, 1H), 4.51-4.49 (m, 2H), 4.39 (m, 2H), 3.86-3.84 (m, 2H), 3.43 (s, 3H), 3.32-3.27 (m, 1H), 2.70 (m, 2H), 2.59-2.55 (m, 2H), 1.64-1.54 (m, 6H), 1.17 (m, 3H), 1.01-0.92 (m, 3H).

Example 51 (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(3-methyloxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.1, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 20 and R¹, R², R³, R⁶ and R⁷ correspond to row A-61 of Table A)

ESI-MS [M+H⁺]=760.4;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 8.14-8.12 (m, 1H), 7.88-7.86 (m, 2H), 7.83-7.81 (m, 1H), 7.75-7.73 (m, 1H), 7.69-7.68 (m, 2H), 7.04-7.01 (m, 1H), 6.70-6.68 (m, 1H), 6.66 (m, 1H), 4.37-4.34 (m, 2H), 4.19-4.11 (m, 2H), 4.09-4.08 (m 2H), 3.85 (s, 3H), 3.44 (s, 3H), 3.20 (m, 3H), 3.13-3.12 (m, 2H), 2.55-2.53 (m, 2H), 2.35 (m, 3H), 1.17-1.13 (m, 1H), 1.99-1.95 (m, 2H), 1.67-1.66 (m, 2H), 1.39-1.35 (m, 2H), 1.23 (s, 3H), 1.07-1.04 (m, 3H).

Example 52

(S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(3-methyloxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide, 2 trifluoroacetic acid

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 20 and R¹, R², R³, R⁶ and R⁷ correspond to row A-61 of Table A)

ESI-MS [M+H⁺]=746.2.

Example 53 N—((S)-5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(2-methyloxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide, 2 trifluoroacetic acid

(S-Enantiomer of the compound of formula I.4, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 21 and R¹, R², R³, R⁶ and R⁷ correspond to row A-61 of Table A)

ESI-MS [M+H⁺]=746.4.

Example 54 (S)—N-(5-cyano-3-(2,5-dimethoxyphenyl)-1-((2,4-dimethoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide

(S-Enantiomer of the compound of formula I.16, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 1 and R¹, R², R³, R⁶ and R⁷ correspond to row A-61 of Table A)

ESI-MS [M+H⁺]=761.2;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 7.89 (d, 1H), 7.84 (d, 1H), 7.77 (dd, 1H), 7.65 (d, 1H), 7.61 (s, 1H), 7.03 (d, 1H), 6.91 (m, 2H), 6.68 (dd, 1H), 6.66 (d, 1H), 4.50 (t, 2H), 4.38 (t, 2H), 3.85 (s, 3H), 3.73 (s, 3H), 3.55 (s, 3H), 3.50 (s, 3H), 3.31 (m, overlapped with H₂O), 3.18 (m, 4H), 2.70 (m, 2H), 2.37 (m, 4H), 2.15 (m, 1H), 1.68 (m, 4H), 1.38 (m, 2H).

Example 55 (S)—N-(5-cyano-3-(2,5-dimethoxyphenyl)-1-((2,4-dimethoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxamide

(S-Enantiomer of the compound of formula I.18, wherein R^(8a), R^(8b), R^(8c), R^(8d), R^(9a), R^(9b), R^(9c), R^(9d), R^(10a), R^(10b) and R^(10c) are as defined in Table 61 and R¹, R², R³, R⁶ and R⁷ correspond to row A-61 of Table A)

ESI-MS [M+H⁺]=760.2;

¹H-NMR (600 MHz; DMSO-d₆), δ [ppm]: 7.89 (d, 1H), 7.86 (d, 1H), 7.76 (dd, 1H), 7.64 (d, 1H), 7.58 (s, 1H), 7.13 (d, 1H), 6.94 (d, 1H), 6.89 (dd, 1H), 6.66 (dd, 1H), 6.65 (m, 1H), 4.50 (t, 2H), 4.38 (m, 2H), 3.83 (s, 3H), 3.82 (m, 2H), 3.73 (s, 3H), 3.57 (s, 3H), 3.49 (s, 3H), 3.29 (m, 2H), 2.69 (m, 2H), 2.53 (m, overlapped with DMSO) 1.63 (m, 2H), 1.53 (m, 4H), 1.09-0.89 (m, 3H).

III. Determination of the Biological Activity III.1 In Vitro Experiments 1. Vasopressin V1b Receptor Binding Assay: Substances:

The test substances were dissolved in a concentration of 5 mM in 100% DMSO and further diluted to 5×10⁻⁴ M to 5×10⁻⁹ M. These serial DMSO predilutions were diluted 1:10 with assay buffer. The substance concentration was further diluted 1:5 in the assay mixture resulting in 2% DMSO in the mixture. All dilutions were performed in a Biomek NX automation workstation (Beckman)

Membrane Preparation:

CHO-K1 cells with stably expressed human vasopressin V1b receptor (clone 3H2) were harvested and homogenized in 50 mM Tris-HCl and in the presence of protease inhibitors (Roche complete Mini #1836170) using a Polytron homogenizer at intermediate setting for 2×10 seconds, and subsequently centrifuged at 40 000×g for 1 h. The membrane pellet was again homogenized and centrifuged as described and subsequently taken up in 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquid nitrogen at −190° C.

Binding Assay:

The binding assay was carried out by the method based on that of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

The incubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (200 μl), membranes (26 μg protein in incubation buffer) from CHO-K1 cells with stably expressed human V1b receptors (cell line hV1b_(—)3H2_CHO) were incubated with 1.5 nM ³H-AVP (8-Arg-vasopressin, PerkinElmer, NET 800) in incubation buffer (50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4) (total binding) or additionally with increasing concentrations of test substance (displacement experiment). The nonspecific binding was determined with 1 μM AVP (Fluka 94836). All determinations were carried out as duplicate determinations. After incubation (60 minutes at room temperature), the free radioligand was filtered off by vacuum filtration (Tomtec Mach III) through Wathman GF/B glass fiber filter plates (UniFilter, PerkinElmer 6005177). The liquid scintillation measurement took place in a Microbeta TriLux 12 (Wallac).

Analysis:

The binding parameters were calculated by nonlinear regression in SAS. The algorithms of the program operate in analogy to the LIGAND analysis program (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239 (1980)). The Kd of ³H-AVP for the recombinant human V1b receptors is 0.4 nM and was used to determine the Ki.

2. Vasopressin V1a Receptor Binding Assay: Substances:

The test substances were dissolved in a concentration of 5 mM M in DMSO. Further dilution of these DMSO solutions took place as described for V1b.

Membrane Preparation:

CHO-K1 cells with stably expressed human vasopressin V1a receptor (clone 5) were harvested and homogenized in 50 mM Tris-HCl and in the presence of protease inhibitors (Roche complete Mini #1836170) using a Polytron homogenizer at intermediate setting for 2×10 seconds, and subsequently centrifuged at 40 000×g for 1 h. The membrane pellet was again homogenized in a High-Pressure-Homogenizer, Polytec 50K at 1500 PSI (Heinemann, Germany) and subsequently taken up in 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquid nitrogen at −190° C.

Binding Assay:

The binding assay was carried out by the method based on that of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

The incubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (200 μl), membranes (40 g protein in incubation buffer) from CHO-K1 cells with stably expressed human V1a receptors (cell line hV1a_(—)5_CHO) were incubated with 0.04 nM ¹²⁵I-AVP (8-Arg-vasopressin, PerkinElmer NEX 128) in incubation buffer (50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4) (total binding) or additionally with increasing concentrations of test substance (displacement experiment). The nonspecific binding was determined with 1 μM AVP (Fluka 94836). Duplicate determinations were carried out.

After incubation (60 minutes at room temperature), the samples were processed as described for V1b.

Analysis:

The binding parameters were calculated by nonlinear regression in SAS. The algorithms of the program operate in analogy to the LIGAND analysis program (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239 (1980)). The Kd of ¹²⁵I-AVP for the recombinant hV1a receptors was determined in saturation experiments. A Kd of 1.33 nM was used to determine the Ki.

3. Oxytocin Receptor Binding Assay Substances:

The substances were dissolved in a concentration of 5 mM in DMSO and diluted further as described for V1b.

Cell Preparation:

Confluent HEK-293 cells with transiently expressing recombinant human oxytocin receptors were centrifuged at 750×g at room temperature for 5 minutes. The residue was taken up in ice-cold lysis buffer (50 mM Tris-HCl, 10% glycerol, pH 7.4 and Roche complete protease inhibitor) and subjected to an osmotic shock at 4° C. for 20 minutes. The lyzed cells were then centrifuged at 750×g at 4° C. for 20 minutes, the residue was taken up in incubation buffer, and aliquots of 10⁷ cells/ml were prepared. The aliquots were frozen at −80° C. until used.

The incubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (200 μl), ghosts corresponding to 5×10⁴ cells (HEK-293 cells expressing transiently human OT receptors) were incubated with 3H-oxytocin (PerkinElmer NET858) in incubation buffer (50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4) (total binding) or additionally with increasing concentrations of test substance (displacement experiment). The nonspecific binding was determined with 1 M A-797879 (AbbVie, Ludwigshafen, Germany). Duplicate determinations were carried out. After incubation (60 minutes at room temperature), the samples were processed as described for V1b.

Binding Assay: Analysis:

The binding parameters were calculated by nonlinear regression analysis (SAS) in analogy to the LIGAND program of Munson and Rodbard (Analytical Biochem 1980; 107: 220-239). The Kd of ³H-oxytocin for the recombinant hOT receptors is 7.6 nM and was used to determine the Ki.

4. Determination of the Microsomal Half-Life:

The metabolic stability of the compounds of the invention was determined in the following assay.

The test substances were incubated in a concentration of 0.5 μM as follows: 0.5 μM test substance are preincubated together with liver microsomes from different species (from rat, human or other species) (0.25 mg of microsomal protein/ml) in 0.05 M potassium phosphate buffer of pH 7.4 in microtiter plates at 37° C. for 5 min. The reaction is started by adding NADPH (1 mg/mL). After 0, 5, 10, 15, 20 and 30 min, 50 μl aliquots are removed, and the reaction is immediately stopped and cooled with the same volume of acetonitrile. The samples are frozen until analyzed. The remaining concentration of undegraded test substance is determined by MSMS. The half-life (T½) is determined from the gradient of the signal of test substance/unit time plot, it being possible to calculate the half-life of the test substance, assuming first order kinetics, from the decrease in the concentration of the compound with time. The microsomal clearance (mCl) is calculated from mCl=ln 2/T½/(content of microsomal protein in mg/ml)×1000 [ml/min/mg] (modified from references: Di, The Society for Biomoleculur Screening, 2003, 453-462; Obach, DMD, 1999 vol 27. N 11, 1350-1359).

5. Methods for In Vitro Determination of the Cytochrome P450 (CYP) Inhibition Luminescent Substrates for 2C9 and 3A4:

0.4 mg/ml human liver microsomes are preincubated with the test substances to be investigated (0-20 M), the CYP-specific substrates, in 0.05 M potassium phosphate buffer of pH 7.4 at 37° C. for 10 min. The Cyp-specific substrate for CYP 2C9 is luciferin H, and for CYP 3A4 is luciferin BE. The reaction is started by adding NADPH. After incubation at RT for 30 min, the luciferin detection reagent is added, and the resulting luminescence signal is measured (modified from reference: Promega, Technical Bulletin P450-GLO™ Assays).

Midazolam CYP 3A4 Time-Dependent Inhibition

The assay consists of 2 parts. Firstly, the test substance is preincubated with the liver microsomes (with NADPH=preincubation, then addition of the substrate; in the second part the substrate and the test substance are added simultaneously=coincubation.

Preincubation:

0.05 mg/ml microsomal protein (human liver microsomes) are preincubated with 0-10 M (or 50 M) test substance in 50 mM potassium phosphate buffer for 5 min. The reaction is started with NADPH. After 30 min 4 M midazolam (final concentration) are added, and incubation is continued for 10 min. 75 l of the reaction solution are removed after 10 min, and stopped with 150 l of acetonitrile solution.

Coincubation:

0.05 mg/ml microsomal protein (human liver microsomes) are preincubated with 4 μm midazolam (final concentration) and 0-10 μM (or 50 μM) test substance in 50 mM potassium phosphate buffer for 5 min. The reaction is started with NADPH. 75 μl of the reaction solution are removed after 10 min and stopped with 150 μl of acetonitrile solution. The samples are frozen until the MSMS analysis (modified from references: Obdach, Journal of Pharmacology & Experimental Therapeutics, Vol 316, 1, 336-348, 2006; Walsky, Drug Metabolism and Disposition Vol 32, 6, 647-660, 2004).

6. Method for Determining the Solubility in Water (in mg/ml)

The solubility in water of the compounds of the invention can be determined for example by the so-called shake flask method (as specified in ASTM International: E 1148-02, Standard test methods for measurement of aqueous solubility, Book of Standards Volume 11.05.). This entails an excess of the solid compound being put into a buffer solution with a particular pH (for example phosphate buffer of pH 7.4), and the resulting mixture being shaken or stirred until equilibrium has been set up (typically 24 or 48 hours, sometimes even up to 7 days). The undissolved solid is then removed by filtration or centrifugation, and the concentration of the dissolved compound is determined by UV spectroscopy or high pressure liquid chromatography (HPLC) by means of an appropriate calibration plot.

7. Results

The results of the receptor binding investigations are expressed as receptor binding constants [K_(i)(V1b)] or selectivities [K_(i)(V1a)/K_(i)(V1b)]. The results of the investigation of the metabolic stability are indicated as microsomal clearance (mCl).

The compounds of the invention show very high affinities for the V1b receptor in these assays (maximally 100 nM, or maximally 10 nM, frequently <1 nM). The compounds also show high selectivities vis-à-vis the V1a receptor and a good metabolic stability, measured as microsomal clearance.

The results are listed in table C. The numbers of the compounds refer to the synthesis examples.

TABLE C Example K_(i)(h-V1b)* [nM] K_(i)(h-V1a)/K_(i)(h-V1b) 1 +++ +++ 2 ++ ++ 3 ++ 4 + 5 ++ 6 ++ +++ 7 +++ 7A +++ +++ 8 ++ +++ 9 ++ +++ 10 +++ +++ 11 +++ +++ 12 + ++ 13 + +++ 14 ++ ++ 15 ++ +++ 16 + 17 + ++ 18 + + 19 + +++ 21 + +++ 24 + +++ 25 ++ +++ 26 ++ +++ 27 +++ +++ 28 + +++ 29 ++ + 30 ++ +++ 31 + +++ 32 + +++ 33 ++ +++ 34 + ++ 35 ++ +++ 36 ++ +++ 37 +++ +++ 38 + +++ 39 +++ 40 ++ + 43 + + 44 ++ +++ 46 + +++ 47 + ++ 49 ++ +++ 50 + ++ 51 ++ +++ 52 ++ +++ 53 ++ ++ 54 +++ ++ 55 +++ + *h = human

Key:

K_(i)(h-V1b) K_(i)(h-V1a)/K_(i)(h-V1b) + >10-100 nM  10-<25 ++    1-10 nM 25-75 +++     <1 nM >75

III.2 Determination of Preclinical In Vivo Efficacy 1. Methods Animals

Male NMRI mice (Janvier, Le Genest-St-Isle, France) were used for stress-induced Adrenocorticotropic hormone (ACTH) release. Adult male Wistar rats (175-220 g body weight upon arrival) were obtained from Harlan Inc. (Indianapolis, Ind.). For the forced swim test, male Sprague Dawley rats (100-120 g body weight upon arrival) were obtained from Janvier (Le Genest-St-Isle, France). The animals were acclimatized to the animal facilities for at least one week before the start of the experimental procedures. Animals were maintained in a controlled environment on a 12:12 hour light dark schedule (lights on 06:00 h for rats in Vogel conflict test and 05:30 h for rats in forced swim test). Experimental procedures took place during the illuminated phase of the light/dark cycle. Food and water were available ad libitum, except for the Vogel conflict test, where the animals were submitted to a water deprivation regimen as described below. The experiments were performed in compliance with the German Animal Protection law (Tierschutzgesetz, Neufassung vom 25.05.1998), the EC directive 86/609 (J of the EC No. L358/1 dated 18 Dec. 1986), Abbott's Institutional Animal Care and Use Committee and the National Institute of Health Guide for Care and Use of Laboratory Animals guidelines in facilities fully accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care (AAALAC).

Tested Compound

The compound of example 21 was used in the below-described tests.

1.1 Stress-Induced ACTH Release

Arginine vasopressin (AVP), a key regulator of the HPA axis, is a cyclic peptide that is synthesized in the hypothalamus. Vasopressin is released from the median eminence into the pituitary portal circulation where it activates HPA activity by stimulation of the pituitary V1B receptor. This results in an increased adrenocorticotropin (ACTH) release which in turn enhances the release of corticosterone in rodents and cortisol in humans from the adrenal glands. Dysregulation of the HPA axis is common in major depression including elevated AVP, increased responsiveness to AVP, as well as either increased or decreased overall HPA axis activity or responsiveness. Therefore, antagonism of the V1B receptor is a potential target for therapeutic intervention.

Animals were subjected to single housing in Type II cages three days before the experiment. At least one day before the experiment they were transferred from the animal facility into the experimental room where they were housed in Scantainers (Type D, Scanbur Ltd., Demark) until the next day. The compound of example 21 or vehicle were applied intraperitoneally (i.p.) 1 hour before the animals were transferred into perforated transparent plastic tubes (diameter 2.5 cm) for a period of 15 minutes to expose them to restraint stress. Non-stressed control animals were left in their home cage for the same time. Thereafter the mice were anaesthetized with isoflurane and blood samples were taken by cardiac puncture. Immediately after blood sampling and still under anesthesia animals were sacrificed by cervical dislocation. Further processing of the blood samples to generate plasma and the determination of ACTH and corticosterone was performed.

The blood was collected in 1.3 mL blood sampling vials containing potassium EDTA (Sarstedt, Nümbrecht, Germany) and 10 L aprotinin solution (saline solution, 3-7 TIU [trypsin inhibitor units]/mg protein; Sigma-Aldrich, Germany). The samples were centrifuged at 2500×g for 20 minutes to obtain the plasma. ACTH concentrations were measured by an ELISA (enzyme-linked immuno sorbent assay) for ACTH (IBL Hamburg, Germany). Prior to the ELISA, samples were diluted 2.5-fold with calibrator A (Zero Calibrator; IBL Hamburg, Germany) provided with the ELISA kit.

1.2 Vogel Conflict Test

The Vogel conflict test is a well-validated animal model to detect compounds with anxiolytic properties. In this model, water-deprived animals face the conflict of receiving a mild shock when they drink water from a metal spigot. Anxiolytic compounds tested in this model induce a significant increase in the number of punished responses. Rats were water-deprived for 48 h before testing. After 24 h of water deprivation, rats were habituated to the testing chambers (Coulbourn Instruments, Whitehall, Pa.) and allowed to drink for 15 min (training session), with an additional 15 min drinking in their home cages. Water deprivation then continued for another 24 h. On the test day, rats were placed in the chambers with access to the water spigot. Every 20 licks, they received one shock (0.5 mA, 1 s duration) delivered through the drinking tube. The number of punished responses was automatically recorded for each rat during 5 min of testing. The compound of example 21 was tested at the doses of 3, 10 and 30 mg/kg i.p. It was administered once on the testing day, 30 minutes before the test.

1.3 Forced Swim Test

The forced swim test has been developed to evaluate antidepressant compounds. Its usefulness is based on the observation that efficacy is seen with many different classes of antidepressant compounds as well as electroconvulsive shock. Forced swim tests are often used for the screening of new antidepressant drugs, but have also been used to investigate depressive-like behavior induced by drugs.

The forced swim test consisted of a pre-test and a test swim. Rats were individually placed for 15 min into cylinders (height: 40 cm, diameter: 21.5 cm) containing 30 cm of water at 25° C. Following this pre-test swim, animals were removed and allowed to dry in a heated enclosure before returning to their home cages. Twenty-four hours later, rats were submitted to the test swim, in which they were placed again in the cylinder for 5 min. Test swims were recorded on videotape and subsequently used for analysis. Latency to immobility was taken as a measure of efficacy. The compound of example 21 was tested in the forced swim test at the doses of 3, 10 and 30 mg/kg i.p. The compound was administered 24, 4 and 0.5 hours before testing, with the first injection given 15 minutes after the pre-swim session on Day 1.

2. Results

FIG. 1 shows ACTH release dependent on the administered dose rate of the compound of example 21.

FIG. 2 shows punishment responses dependent on the administered dose rate of the compound of example 21.

FIG. 3 shows latency to immobility dependent on the administered dose rate of the compound of example 21.

In the figures, the asterisk (*) indicates a statistically significant difference compared to the control.

2.1 Stress-Induced ACTH Release

As FIG. 1 shows, injection of the compound of example 21 significantly blocked stress-induced ACTH release. Example 21 significantly blocked the stress response at 10 and 30 mg/kg.

2.2 Vogel Conflict Test

As FIG. 2 shows, application of the compound of example 21 resulted in dose dependent anxiolytic-like efficacy in Vogel conflict. The compound of example 21 showed significant effect at 10 and 30 mg/kg.

2.3 Forced Swim Test

As FIG. 3 shows, application of the compound of example 21 increased the latency to immobility in the forced swim test. The compound of example 21 showed a significant antidepressant-like effect at 10 mg/kg. 

1. A compound of formula I

wherein X¹ and X² are N or CH, with the proviso that X¹ and X² are not simultaneously N; X³ is a bond, C₁-C₄-alkylene, C₁-C₄-haloalkylene or CO; X⁴ is N or CH; X⁵ is C—R¹ or N; R¹ and R², independently of each other, are selected from hydrogen, halogen, cyano, C₁-C₃-alkyl, fluorinated C₁-C₃-alkyl, C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy and fluorinated C₁-C₃-alkoxy; R³ is selected from hydrogen, halogen, cyano, C₁-C₃-alkyl, fluorinated C₁-C₃-alkyl, C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy, fluorinated C₁-C₃-alkoxy and hydroxyl; R⁴ is selected from C₁-C₃-alkoxy; R⁵ is selected from hydrogen and C₁-C₃-alkoxy; R⁶ is selected from cyano and halogen; R⁷ is selected from hydrogen, halogen and cyano; R⁸ and R⁹, independently of each other and independently of each occurrence, are selected from halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, with the proviso that R⁸ and R⁹ are not halogen, C₁-C₄-alkoxy or C₁-C₄-haloalkoxy if they are bound to a carbon atom in α-position to a nitrogen ring atom; or two non-geminal radicals R⁸ form together a group —(CH₂)_(n)—, where n is 1, 2, 3 or 4, where 1 or 2 hydrogen atoms in this group may be replaced a methyl group; or two non-geminal radicals R⁹ form together a group —(CH₂)_(n)—, where n is 1, 2, 3 or 4, where 1 or 2 hydrogen atoms in this group may be replaced a methyl group; each R¹⁰ is independently selected from halogen, C₁-C₄-alkyl and C₁-C₄-haloalkyl; a is 0, 1, 2, 3 or 4; b is 0, 1, 2, 3 or 4; and c is 0, 1, 2, 3 or 4; and the N-oxides, stereoisomers and pharmaceutically acceptable salts thereof, and the compound of the formula I, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope.
 2. The compound of claim 1, wherein at least one hydrogen atom has been replaced by a deuterium atom.
 3. The compound of claim 1, where R¹, R² and R³, independently of each other, are selected from hydrogen, halogen, cyano, C₁-C₃-alkyl, fluorinated C₁-C₃-alkyl, C₁-C₃-hydroxyalkyl, C₁-C₃-alkoxy and fluorinated C₁-C₃-alkoxy.
 4. The compound of claim 3, where R¹, R² and R³, independently of each other, are selected from hydrogen, fluorine, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy and trifluoromethoxy.
 5. The compound of claim 4, where R¹, R² and R³, independently of each other, are selected from hydrogen, fluorine, cyano, methyl and methoxy.
 6. The compound of claim 5, where R¹ is selected from hydrogen, fluorine, methyl and methoxy.
 7. The compound of claim 5, where R² is selected from hydrogen, cyano, methoxy and fluorine.
 8. The compound of claim 5, where R² is methyl.
 9. The compound of claim 5, where R³ is selected from hydrogen, fluorine and methyl.
 10. The compound of claim 1, where R⁴ is selected from methoxy and ethoxy.
 11. The compound of claim 1, where R⁴ is isopropoxy.
 12. The compound of claim 1, where R⁵ is hydrogen or methoxy.
 13. The compound of claim 1, where R⁶ is selected from cyano, fluorine and chlorine.
 14. The compound of claim 1, where R⁷ is selected from hydrogen and fluorine.
 15. The compound of claim 1, where each R⁸ is independently selected from halogen and C₁-C₄-alkyl, preferably from F, Cl and CH₃, with the proviso that R⁸ is not halogen if it is bound to a carbon atom in α-position to a nitrogen ring atom, or two non-geminal radicals R⁸ form together a group —CH₂—.
 16. The compound of claim 15, where two non-geminal radicals R⁸ form together a group —CH₂—.
 17. The compound of claim 16, where the two non-geminal radicals R⁸ forming together a group —CH₂— are bound in 2- and 5-position, relative to the 1-position of X¹.
 18. The compound of claim 1, where each R⁹ is independently selected from halogen and C₁-C₄-alkyl, preferably from F, Cl and CH₃, with the proviso that R⁹ is not halogen if it is bound to a carbon atom in α-position to a nitrogen ring atom, or two non-geminal radicals R⁹ form together a group —CH₂—.
 19. The compound of claim 18, where two non-geminal radicals R⁹ form together a group —CH₂—.
 20. The compound of claim 19, where the two non-geminal radicals R⁹ forming together a group —CH₂— are bound in 2- and 5-position, relative to the 1-position of X².
 21. The compound as of claim 1, where each R¹⁰ is independently selected from halogen and C₁-C₄-alkyl.
 22. The compound of claim 1, where X³ is a bond or CH₂.
 23. The compound of claim 22, where X³ is a bond.
 24. The compound of claim 1, where X⁴ is N.
 25. The compound of claim 1, where X⁴ is CH.
 26. The compound of claim 1, where X⁵ is C—R¹.
 27. The compound of claim 1, where X⁵ is N.
 28. The compound of claim 1, where a is 0, 1 or
 2. 29. The compound of claim 1, where b is 0, 1 or
 2. 30. The compound of claim 1, where c is 0, 1 or
 2. 31. The compound of claim 1, selected from the group consisting of: (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide; (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide; N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide; N-(5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)indolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide; (S)—N-(5-cyano-1-((4-cyanophenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide; (S)—N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((2-fluoro-4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide; N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide; (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide; (S)—N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((5-fluoro-2,4-dimethoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide; (S)—N-(1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide; (S)—N-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide; (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxamide; (S)—N-(5-cyano-1-((4-cyanophenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide; (S)—N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide; (S)—N-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide; N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide; N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(4-(oxetan-3-yl)piperazin-1-yl)piperidine-1-carboxamide; N—((S)-5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-((1S,4S)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)piperidine-1-carboxamide; (S)—N-(5-cyano-3-(2-ethoxypyridin-3-yl)-1-((4-methoxy-2,3-dimethylphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide; (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-ylmethyl)piperidin-4-yl)piperazine-1-carboxamide; N-[(3S)-1-(benzenesulfonyl)-5-cyano-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[4-(oxetan-3-yl)piperazin-1-yl]piperidine-1-carboxamide; N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide; N-[(3S)-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-5,6-difluoro-2-oxo-indolin-3-yl]-4-[4-(oxetan-3-yl)piperazin-1-yl]piperidine-1-carboxamide; N-[(3R)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide; N-[(3S)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-(4-methoxyphenyl)sulfonyl-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide; N-[(3S)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-[(5-methoxy-2-pyridyl)sulfonyl]-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide; N-[(3S)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide; N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide; N-[(3S)-5-cyano-3-(2-ethoxy-3-pyridyl)-1-(4-fluorophenyl)sulfonyl-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide; N-[(3S)-5-cyano-3-(2-methoxy-3-pyridyl)-1-[(5-methoxy-2-pyridyl)sulfonyl]-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide; N-[(3S)-5-cyano-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide; N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[4-(oxetan-3-yl)piperazin-1-yl]piperidine-1-carboxamide; N-[(3S)-5-cyano-3-(2-ethoxy-5-methoxy-phenyl)-1-[(5-methoxy-2-pyridyl)sulfonyl]-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide; N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-5-methoxy-phenyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide; N-[(3S)-5-cyano-1-(4-methoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide; N-[(3S)-5-cyano-3-(2-ethoxy-5-methoxy-phenyl)-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide; N-[(3S)-5-cyano-1-(4-methoxyphenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide; N-[(3S)-5-cyano-1-(4-fluoro-2-methoxy-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide; N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-5-[1-(oxetan-3-yl)-4-piperidyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide; N-[(3S)-5-cyano-3-(2-methoxy-3-pyridyl)-1-[(5-methoxy-2-pyridyl)sulfonyl]-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide; N-[(3S)-5-cyano-1-(4-fluorophenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide; N-[(3S)-5-cyano-1-(5-fluoro-2,4-dimethoxy-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide; N-[(3S)-5-cyano-1-(5-fluoro-2,4-dimethoxy-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperidine-1-carboxamide; N-[(3S)-5-cyano-1-(4-cyanophenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide; N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-isopropoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide; N-[(3S)-5-cyano-3-(2-methoxy-3-pyridyl)-2-oxo-1-(p-tolylsulfonyl)indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide; N-[(3S)-5-cyano-1-(2-methoxy-4-methyl-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide; N-[(3S)-5-cyano-1-(4-cyano-2-fluoro-phenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide; N-[(3S)-5-cyano-1-(2,4-difluorophenyl)sulfonyl-3-(2-methoxy-3-pyridyl)-2-oxo-indolin-3-yl]-4-[1-(oxetan-3-yl)-4-piperidyl]piperazine-1-carboxamide; (S)—N-(5-cyano-1-((2-methoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxamide; (S)—N-(5-cyano-3-(2-methoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)indolin-3-yl)-1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxamide; (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(3-methyloxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide; (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(3-methyloxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide; N—((S)-5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(1-(2-methyloxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide; (S)—N-(5-cyano-3-(2,5-dimethoxyphenyl)-1-((2,4-dimethoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)piperazine-1-carboxamide; (S)—N-(5-cyano-3-(2,5-dimethoxyphenyl)-1-((2,4-dimethoxyphenyl)sulfonyl)-2-oxoindolin-3-yl)-1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxamide; and the N-oxides, stereoisomers, racemates and/or pharmaceutically acceptable salts thereof.
 32. A pharmaceutical composition comprising at least one compound of the formula I of claim 1 and/or an N-oxide, a stereoisomer or at least one pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
 33. (canceled)
 34. (canceled)
 35. (canceled)
 36. A method for the treatment and/or prophylaxis of diseases selected from the group consisting of vasopressin-related diseases, diabetes, insulin resistance, nocturnal enuresis, incontinence and diseases in which impairments of blood clotting occur, hypertension, pulmonary hypertension, heart failure, myocardial infarction, coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty), ischemias of the heart, impairments of the renal system, edemas, renal vasospasm, necrosis of the renal cortex, hyponatremia, hypokalemia, Schwartz-Bartter syndrome, impairments of the gastrointestinal tract, gastritic vasospasm, hepatocirrhosis, gastric and intestinal ulcers, emesis, emesis occurring during chemotherapy, travel sickness; affective disorders; anxiety disorders and stress-dependent anxiety disorders; memory and cognitive impairments such as Alzheimer's disease, mild cognitive impairment and cognitive impairment associated with schizophrenia; psychoses and psychotic disorders; Cushing's syndrome and other stress-dependent diseases; sleep disorders; depressive disorders, such as major depression, seasonal depression, bipolar disorders, treatment-resistant depression, dysthymic disorders or childhood onset mood disorders; vasomotor symptoms, thermoregulatory dysfunctions; drug or pharmaceutical dependencies, dependencies mediated by other factors; stress caused by withdrawal of one or more factors mediating the dependence; stress-induced relapses into drug or pharmaceutical dependencies and/or dependencies mediated by other factors, such as alcohol use disorder, alcohol intoxication, alcohol withdrawal and unspecified alcohol-related disorder; drug-use disorders; schizophrenia and psychosis; and/or for delaying micturition, the method comprising administering an effective amount of at least one compound of the formula I of claim 1, or of at least one N-oxide, stereoisomer or pharmaceutically acceptable salt thereof, to a patient in need thereof.
 37. (canceled)
 38. (canceled) 